PROJECTS STARTED IN 2015
The impact of smoking and smoking cessation on skeletal muscle structure and function
PI: Prof. Thierry Troosters, KU Leuven, Belgium; co-PI: Dr. Ir. Hans Degens, MMU, UK
DC: Tom Aijme
Cigarette packages contain threatening labels like ‘Smoking Kills’ and ‘Smoking clogs the arteries and causes heart attacks and stroke’. These labels do indicate a tragic truth as smoking is a major risk factor for the development of cancer, cardiovascular diseases respiratory disorders like chronic obstructive pulmonary disease later in life. Smoking has also been identified as a risk factor for the development of sarcopenia in community dwelling elderly men. Yet, in 2010 the prevalence of daily or any current smoking in the 28 countries of the European Union (EU) amounted to 27.8% in females and 41.4% in males (European Respiratory White Book, 2013). It should be noted that these disastrous effects of smoking develop unperceivably slow and show their devastating effects on the patient’s health only later in life, a phenomenon sometimes referred to as ‘the smoking time-bomb’. To make matters worse smoking does have immediate positive effects, such as calming and an increased alertness. It would thus help if one could also show immediate negative effects of smoking, and even better still, that these immediate negative effects can be reversed by smoking cessation. Carbon monoxide and cyanide are constituents of cigarette smoke impair oxygen delivery and the function of the respiratory chain, which could contribute to muscle fatigue. Here we will study the impact of smoking and smoking cessation in humans and a smoking-mouse model on skeletal muscle, lung, vascular and mitochondrial function and hypothesise that smoking cessation readily reverses the deterimental effect of smoking on muscle and vascular function. If smoking cessation does lead to an immediate improvement in skeletal muscle function this could help smoking cessation in patients with muscle weakness referred to rehabilitation programs, but still actively smoking, or those admitted to hospital and suffering from acute muscle deterioration yet struggling with smoking cessation.
Ageing of the on-line control of posture and movement
PI: prof.dr Jeroen B.J. Smeets, MOVE, Netherlands; co-PI: prof. dr Jaak Duysens, KU Leuven, Belgium
DC: Yajie Zhang
It is well known that vision helps to stabilise a standing person’s posture. A consequence of this is that one sways with the surrounding if the latter moves. It has also been established that goal-directed movements towards a static target are influenced at a very short latency by motion of the target as well as by motion in the surrounding. We propose that these responses are related to balance control. As the control of both balance and hand movements are known to decline in the elderly, we will study how their interaction develops during ageing. To do so we will determine the magnitude of the influence of various kinds of motion of the surrounding on both pointing and locomotion in various age groups. To determine to what extent the effects of motion of the visual surrounding are actually based on its effect on posture, we will compare the effects with those of two other perturbations of posture. To do so we will perturb vestibular information by galvanic stimulation, and proprioceptive information by vibration of the Achilles tendon. The results of this study will be implemented in the balance training software that is being developed in a running MOVE-AGE project (van Dieën).
Interplay of genetic and epi-genetic markers of sarcopenia
PI: prof.dr. Martine Thomis , KU Leuven, Belgium: co-PI: Dr Christopher Morse, MMU, UK
DC: Lingxiao He
Individual variation in the degree of functional decline with aging is probably partially determined by the genetic make up of the individual. Studies on the heritable part of muscular mass and strength have mostly been done in younger twin studies. The field of genetic epidemiology in movement sciences has further evolved to the study of genetic sequence variation, via linkage and candidate gene association studies. Several gene variants have been associated with muscle mass (or CSA) and several muscular strength phenotypes, again with most focus on younger samples. Reports on the study of multiple genetic variants or genetic profiles have been more focused on the power to discriminate elite sports performance (Ruiz et al., 2010; Hughes et al., 2011). Well-designed studies in older or frail populations on genetic variation in muscle mass/muscle strength & functionality phenotypes are limited and mostly cross-sectional in nature (reviewed in Garatachea and Lucia, 2013). A first WP in this project aims to test the predictive power of a genotypic predisposition score –based on a set of 22 candidate-gene variants- in an 11 months intervention program in 65yr+ seniors. Individual differences in the strength and muscle mass responses after training and in a one and 7 year follow-up measurement are already available (Kennis et al., 2013b) and will be associated with a multi-SNP composed ‘Genetic predisposition score’ (GPS-score).
Changes in muscle size and function by aging are multifactorial and caused by the interaction between genomic and environmental conditions, for which the interface of epigenetics may be a central mechanism. DNA methylation status of gene promoters regulate the expression of genes amongst other epigenetic mechanisms (histone modification, miRNAs, ncRNAs). Recent work has focused on changes in DNA methylation related to the aging process (Ong and Holbrook, 2013) in general and related to frailty more specifically (Collerton et al., 2014). WP2 in this project will explore DNA methylation differences between community-dwelling female elderly and those living in assisted residential homes related to muscle size and function phenotypes. The DNA of the elderly females as phenotyped and genotyped in the project of Dr. Morse (n=212) will be analysed for differences in promoter CpG methylation. The identification of differentially methylated CpGs (dmCpG) will inform us about important differences in epigenetic regulation of muscle size and function in elderly females.
Mechanics and energetics of walking in old and young adults
PI: dr M. Bobbert, MOVE, Netherlands; co-PI: dr I. Jonkers, KU Leuven, Belgium
DC: Sauvik Das Gupta
Metabolic Cost of Walking (MCoW), defined as metabolic energy used per meter travelled, is an important variable in daily life, because it affects how rapidly people become fatigued and hence determines their functional possibilities. The current proposal is concerned with MCoW in Old Adults (OA, over 70 years of age) as compared to Young Adults (YA, 18-30 years of age). It is well-established that OA have 20-30% higher MCoW than YA. It is also well-established that OA have a different walking pattern than YA. The general aim of the proposed project is to achieve a better understanding of the factors linking walking pattern to MCoW. The specific aim of the project is to understand why OA use more metabolic energy than YA per meter distance travelled. If OA have higher MCoW, they must use more energy to produce a given amount of positive work, lose more energy to the environment, and/or dissipate more energy in eccentric muscle fiber actions. Objectives of the current study are: (1) to describe natural walking patterns (in terms of kinematics, kinetics, EMG), MCoW and musculoskeletal and physiological properties in OA and YA, (2) to determine short-term effects on MCoW of having OA walk like YA, and having YA walk like OA, (3) to determine prolonged training effects of changes in walking parameters on MCoW, (4) to determine effects of (de)stabilization of the body on walking pattern and MCoW, and (5) to estimate energy expenditure in various conditions mentioned above with the help of a musculoskeletal model and determine to what extent differences in estimated energy expenditure explain observed differences in MCoW between OA and YA. With the proposed studies, we will improve our understanding of the factors and underlying mechanisms that cause MCoW to be higher in OA than in YA. This understanding is not only of fundamental interest, it may also help to identify the variables that should be targeted in training to reduce MCoW and thereby enhance an active life style and societal participation of OA.
The genetics of sarcopenia
PI: dr C. Morse, MMU, UK; prof. dr M. Thomis, KU Leuven, Belgium
DC: Praval Khanal
The decline in muscle size with ageing, termed sarcopenia, is accompanied by a decline in muscle strength (Thom et al., 2005). These impairments in muscle function contribute to the age-associated decline in the capacity to perform activities of daily living (ADL). In young adults, as much as 70% of the variability in quadriceps maximal voluntary contraction (MVC) strength and muscle size is heritable (Huygens et al., 2004). In the elderly, the heritability of both muscle size and strength appear lower (Garatachea & Lucia, 2013), and based on genetic association studies remains inconclusive. Indeed, candidate gene variants such as ACTN3 R577X have demonstrated significant associations with muscle size in middle-aged women (Zempo et al., 2010), with no association in older individuals (Delmonico et al., 2008).
However, studies to date have examined single genetic polymorphisms associated with skeletal muscle mass and strength, and primarily involved community-dwelling elderly individuals e.g. (Garatachea et al., 2012), who in terms of ADL may be the least impaired. Adopting a polygenic approach
(Williams & Folland, 2008) to investigate the genetic influence on various properties of skeletal muscle should provide a more complete understanding of sarcopenia, particularly in the eldest, most impaired individuals. Therefore, the aim of this research is to 1) investigate the genetic influence on quadriceps muscle size and strength in elderly females; and 2) investigate whether differences in genotype and muscle phenotypes exist between community-dwelling elderly and those living in assisted residential homes.
In the first phase of the research, the genotype profile of 460 elderly women (>65 years) living independently or in assisted accommodation will be assessed from saliva or venous blood samples. From this initial population, 212 participants will be selected based on homozygosity of a chosen polymorphism (e.g. RR and XX for ACTN3 R577X) and their muscle size and function determined. In the second phase, the polygenic influence on quadriceps muscle size and function in those 212 elderly women will be determined. Finally, the muscle size, strength and polygenic profile of age-matched elderly women living in assisted residential homes will be compared to those who are community-dwelling.
PROJECTS STARTED IN 2014
Aging associated impairment of muscle mechano-sensitivity causing reduced muscle protein synthesis and regeneration
PI: prof. dr A. de Haan, MOVE, Netherlands; co-PI: prof. dr P. Hespel, K.U. Leuven, Belgium
PhD fellow: Mohammad Haroon
Sarcopenia, the age-related loss of muscle mass and muscle strength, is associated with impaired physical function, increased risk of falls, fractures, dependency major health care concern for the aged individual. Hence it is of great importance to prevent muscle atrophy and a reduction in the rate of protein synthesis at high age. Several mechanisms underlying the age related loss of mass have been reported, however their relative contributions to prevent muscle loss remain elusive, let alone the means to maintain muscle mass at old age. It is well known that heavy physical exercise is generally an effective stimulus to enhance protein synthesis and increase muscle fiber cross-sectional area, however in frail, old people such exercise is often dissuaded. Current knowledge suggests that during aging, myofibers and muscle satellite cells (MuSC) become less mechano-sensitive and as a consequence the rate of protein synthesis within myofibers as well as the regenerative potential of the MuSC would be diminished in response to physical exercise. This project aims to uncover whether aging related reductions(s) in mechano-sensitivity apply to the MuSC, the myofiber or both. For this purpose we will culture freshly isolated adult and old mouse MuSCs and overload these cells by subjecting them to cyclic tensile strains or pulsating fluid flow. Furthermore we will test whether aging affects the mechanical loading induced anabolic signaling within myofibers and whether MuSCs are activated. Finally we will explore the effects of moderate physical exercise on changes in muscle fiber signaling pathways and regeneration of damaged myofibers and test whether any positive effects is absent in the aged mice. To evaluate whether aging attenuates the anabolic response in physically active men, biopsies obtained from master athletes will be stained and analyzed for the number of myonuclei and MuSCs. With this project, we expect to elucidate mechano-(chemical) signal transduction mechanisms in aged MuSCs as well as in aged myofibers which explain aging associated atrophy and a reduced muscle potential to hypertrophy. These insights are requisite for discovery of improved therapeutic treatments of sarcopenia.
Optimisation of training programs with respect to muscle adaptations in elderly subjects
PI: prof. dr C. Delecluse, K.U. Leuven, Belgium; co-PI: prof. dr J. van Dieën, MOVE, Netherland
PhD fellow: Remco Baggen
The age-associated decline in muscle mass, also known as sarcopenia, represents a prominent publichealth problem. Sarcopenia has been associated with functional impairment, progressive disability, increased susceptibility to falls and general slowness of movement, making elderly more dependent on others in daily life. Therefore, the development of effective strategies to prevent sarcopenia constitutes an urgent scientific challenge. Exercise programs can positively affect muscle mass. However, the optimal type, intensity, frequency and duration of exercise to enhance muscle mass is still unknown, especially in elderly. This is partly because the exact loading produced by diverse types of exercises on muscle is not known together with a lack of well-designed long-term clinical trials. Therefore, the main aim of the present project is to obtain fundamental and clinical data to optimize exercise programs stimulating muscle in elderly subjects. The first objective is to measure and model muscle loading during both resistance training exercises as well as impact exercises. These results combined with the results of a parallel project quantifying the loading on femoral neck during the same exercises, will lead us to the second and main objective of the current project. The second objective is to design a novel optimized training program with selected exercises that sufficiently stimulate the target tissues (not only muscle mass but also bone) and to assess the clinical implications of this training protocol, based on a one-year randomized controlled trial in a population of communitydwelling elderly above 70 years of age.
Biomechanical changes in articulation of the jaw joint due to aging
PI: prof. dr V. Everts, MOVE (ACTA), Netherlands; co-PI: prof. dr ir. H. van Lenthe, KU Leuven, Belgium
PhD fellow: Fereshteh Mirahmadi
Age-related thinning of articular cartilage is supposed to increase susceptibility for osteoarthritic changes in the temporomandibular joint. The present project will test the hypothesis that this process is caused by an increased stiffening of the cartilage. This stiffening is considered to result in a reduction of the possibilities for metabolic activity of the chondrocytes in the layer near the subchondral bone, followed by a subsequent calcification of this area. This hypothesis will be tested (i) by predicting convection of solutes (required for metabolism of the chondrocytes) in the cartilaginous structures of the human jaw joint during habitual exercise using biomechanical modeling, (ii) by experimental analysis of propagation of solutes in the cartilaginous structures of the jaw joint in response to compressive or shear deformations, and (iii) by quantification of the structural and mechanical changes in aging subchondral bone. Consequently, experimental testing of the environment of chondrocytes relevant for maintenance of cartilage will be combined with biomechanical modeling to predict biomechanical consequences of aging for joint maintenance during habitual loading. The influence of aging will be assessed in the experimental tests by comparing measurements in temporomandibular joints of (i) subjects of different age and (ii) specimen of relatively young material that has been aged artificially using ribose. This project will be unique in a sense that biological mechanisms on a cellular level will be related to the mechanics of habitual human masticatory behavior. Furthermore, vulnerability for acquiring osteoarthritic changes will be related to the normal changes of the cartilaginous extracellular matrix during aging. Finally, the project is directed to fibro-cartilage, which is normally considered as inferior in load bearing capacity, but in the jaw joint has proven to be very sustainable.
Is sedentarism, independent of physical activity and hormonal status, a modulator of healthy ageing?
PI: dr Gladys Onambélé-Pearson, MMU, UK; prof. dr S. Verschueren, KU Leuven, Belgium
PhD fellow: Jorgen Wullems
The recommended levels of physical activity are seldom reached in western societies. In the UK for instance, the cost of care as a consequence of lower than recommended physical activity, is an estimated £10 billion a year to the NHS. ‘Game plan’ (Strategy-Unit and DCMS, 2002) estimated that a 10% increase in physical activity in adults would benefit England, at least £500 million per year and save approximately 6,000 lives a year. New research suggests that, regardless even of leisuretime physical activity, sedentary behaviour itself (e.g. sitting to watch TV or use a computer) is a distinct health risk. Indeed sedentary behaviour has negative effects on metabolic profile, cardiovascular health, psychosocial well-being and stimulates obesity (Tremblay et al., 2010). This has led to the phenomenom coined ‘the active couch potato’, whereby a person may exhibit participation in bouts of medium to high physical activity, yet be highly sedentary in the intervening periods. In older people in particular, sedentarism is a pressing problem as they spend a great deal of time sitting. Here, we aim to advance understanding of the interplay between sedentary vs. activity behaviour, and how this affects musculo-tendinous factors of physical performance in older adults. This will be achieved by measuring activity/inactivity patterns through questionnaires & accelerometers in a cohort of 120-180 older persons (with a wide age range) and determine associations with their musculo-skeletal functioning, cardiovascular health and the ability to carry out habitual daily physical functions (in particular, postural and dynamic balance), which is key for quality of later life. Musculoskeletal and tendon function will be assessed with dymamometry. Cardiovascular function from resting and post-exercise cardiovascular structural and functional characteristics, will also be collected to complement the picture of the impact of sedentary behaviour on this system, and hence align our findings against cardiovascular data from previous studies. Overall, the current proposed program of studies will enable us to identify physical markers of increased musculo-skeletal and/or cardiovascular health risks, based on an older person’s pattern/magnitude of inactivity. Such findings would have the potential of allowing accurate targetting and design of future preventative interventions.
Understanding hand motor control in healthy aging
PI: prof. dr D. Veeger, MOVE, Netherlands; co-PI: dr I. Jonkers, KU Leuven, Belgium
PhD fellow: Mojtaba Mirakhorlo
This project is one of two projects, which have as major objective to increase our understanding in the changing “neuromechanics” of hand motor control with age. In the aging population, quality of hand motor control decreases, due to loss of stability as well as loss of mobility. This occurs in both wrist and fingers. While loss of motor control is a general feature of aging, a number of interacting factors may be held responsible. Normal aging or arthritic phenomena can limit wrist joint mobility. In addition, the biomechanical function of individual muscles and their neurophysiological characteristics within the neuro-musculo-skeletal system may change with age. Different levels of hand function, namely neural control and mechanical muscle interaction are essential in the motor system’s versatility and are approached quantitatively using the combined expertise of the involved research groups. Recently, a musculoskeletalmodel of the hand and wrist has been developed that comprises both extrinsic and intrinsic hand muscles, the extensor mechanism and of course the full complex of wrist- and forearm biomechanics.This model is intended to become a powerful tool in the analysis of hand function and dysfunction and the study of “what if” questions such as the pathophysiology of CMC1 arthrosis, or the effect of tendon transfers in the tetraplegic hand. A generally accepted simplification in the model, as in all large-scale musculoskeletal models, is that neural control of wrist and fingers can be performed independently and that intermuscular and intertendinous connections have an egligible effect on model predictions of joint contact forces and muscle forces. With experimental data using multi-array electromyography(EMG), fingerend point forces and bi-planar ultrasound (project I) in specified hand tasks, we intend to quantify such dependencies and estimate their importance for the development of an age group specific model. In the present project II, the combination of EMG- and force data will be used to develop an EMG-supported (EMG-driven) version of the above described model,suitable for the evaluation of hand motor control in normal aging and age-related hand pathologies.
Interactions between androgen receptor signalling, calcium homeostasis and bone turnover in male mice
PI:prof. dr Dirk Vanderschueren, KU Leuven, Belgium; co-PI: prof. dr N. Bravenboer, MOVE (ACTA), Netherlands
PhD fellow: Bibek Poudel
Male osteoporosis is a neglected problem although men contribute to about 30% of osteoporotic fractures and associated expenditures. Men are protected against osteoporosis compared to women due to increased peak bone and muscle mass and maintenance in old age. Sex steroids (androgens and oestrogens) are the chief regulators of both these effects although the mechanisms of their musculoskeletal effects remain incompletely understood. We have shown that androgen receptor (AR) knock-out abolishes musculoskeletal sexual dimorphism in mice. Direct actions through the AR in osteocytes, osteoblast, osteoclast and satellite cells have been defined using Cre-LoxP technology but these transgenic mouse models do not fully explain the impact of androgens on musculoskeletal homeostasis. Although AR is present in key organs of calcium homeostasis such as kidney and intestine, its role in these organs is unknown. Oestrogens maintain bone mass, increase calcium absorption and reabsorption, but whether AR can exert similar effects remains unknown. Our hypothesis therefore is that AR coordinates calcium, phosphate and vitamin D signalling in intestine and/or kidney to match the demands for peak bone mass development and bone turnover in old age. Therefore, we will subsequently validate and characterize intestinal- and kidney-specific AR knock-out mice (alone and in combination) to study direct actions of androgens on calcium homeostasis, vitamin D metabolism and downstream effects on peak musculoskeletal mass and maintenance in adult male transgenic mice.
PROJECTS STARTED IN 2013
Impaired mobility in aging – The role of antioxidants in improving vascular and muscular function
PI: dr. May Azzawi, IRM, United Kingdom; co-PI: prof.dr. L. Vanhees, K.U. Leuven, Belgium
PhD fellow: Miguel Diaz Gomez
Aging is associated with an impaired adaptive response to resistance exercise, but the precise causal mechanisms remain unclear. Impaired vascular function is one contributor and is characterised by impaired vasodilator function in response to pharmacological and physical stimuli such as shear stress. Of particular relevance, is impaired flow (shear stress) induced dilation (FID), related to endothelial dysfunction, in response to exercise, leading to inadequate tissue perfusion – hence a lower adaptive response to exercise. The endothelial dysfunction at old age may be a consequence of oxidative stress where any reduction of oxidative modifications within the vasculature may reverse some of the age-related impairments of muscular function. The aim of the proposed investigation is to understand how vascular responses can contribute to impaired skeletal muscle responses in aging and whether such parameters could improve subsequent to antioxidant treatment. This research project will be divided into two components: an animal study and a human study. For the animal experiments, femoral arteries from young-adult and old male mice will be isolated and maintained in a viable state in vitro and their endothelial dependent responses characterised, with or without antioxidant supplementation over a 6-week period. The animal studies will also ascertain the relationship between vascular dysfunction, muscle capillarisation and the hypertrophic response of the muscle. The human study will complement the animal study and will involve a randomized double-blind placebo controlled parallel-design trial which will be performed in 60 healthy older men (>65 yrs) to determine whether a 10-week supervised dynamic resistance training program supplemented with resveratrol (an antioxidant, a phytoalexin) will result in 1) enhanced endothelial function and 2) larger muscle hypertrophic responses compared to dynamic resistance training without supplementation. Findings of this research project will have important implications in ascertaining the role of vascular function in improving muscle adaptation to exercise. Furthermore, it will identify oxidative stress as an additional therapeutic target that may enhance endothelial dependent vascular function and consequent muscular adaptations to exercise.
Impacts of cortical (a)symmetry on age-related changes in movement coordination
PI: prof. dr. A. Daffertshofer, MOVE, Netherlands, co-PI: prof.dr. S. Swinnen, K.U. Leuven, Belgium
PhD fellow: Parinaz Babaeeghazvini
The world-famous pianist Vladimir Horowitz completed his final recording four days before his death. The recording consisted of a repertoire Horowitz had never previously recorded. He died in 1989 at the age of 86. In terms of well-tempered bimanual coordination, Horowitz was certainly more an exception than the rule. In fact, for most of us playing the piano forms a major hurdle, irrespective of age, as moving our hands and fingers accurately and independently is not easy. Most probably this difficulty stems from a cross-talk of activity from one side of the body to the other. It is the mere symmetry of the central nervous system that renders the interhemispheric cross-talk prominent, probably more so when movement-related neural activity becomes synchronized.Therefore, unimanual performance, i.e. moving only one hand, requires suppression of the co-activation of the homologous limb through active inhibition of corresponding areas in the brain. This suppression requires a functional interaction that may have to be even better tempered than Horowitz’ piano playing. The functional interaction has to capitalize on the underlying neuro-physiological structure – for the left/right interaction this certainly involves the corpus callosum. With aging, however, the integrity of the corpus callosum decreases, which probably causes age-related difficulties in left/right coordination and increases left/right interference. We intend to examine the relationship between structure-based, functional changes in neural activity and age-related motor deficits. Functional imaging will be used to assess (a)symmetric metabolic changes by contrasting uniand bimanual performances and manipulating, by hypothesis, the degree of behavioral interference. Encephalographic recordings will further serve to assess the accompanying neural synchronization. If successful, our research activities will advance the general understanding of changes in information processing in the brain and, in particular, motor-deficits caused by age-related reorganization of the brain. By this, we hope to contribute to the MOVE-AGE development of scientific knowledge about factors limiting movement organization in the elderly.
Can mechanical loading compensate for aging effects in vitamin D, phosphate and sex hormone metabolism in maintaining bone mass?
PI: prof. dr. P. Lips, MOVE, Netherlands; co-PI: prof.dr. D. Vanderschueren, K.U. Leuven, Belgium
PhD fellow: Ashwini Kumar Nepal
Vitamin D as well as sex hormones play a major role in osteoporosis. Deficiency of sex hormones and vitamin D occur with aging. Phosphate homeostasis is important for normal bone mineralization. The bone derived hormone FGF23 is a major regulator of phosphate homeostasis. FGF23 is produced by osteocytes and binds, in the presence of the co-factor klotho, to the FGF receptor. Its main function is stimulating phosphate excretion and decreasing 1,25(OH)2D3 production in the kidney. Mechanical loading which has a strong anabolic effect on bone inhibits the expression and secretion of FGF23. Because of the strong interrelationships between vitamin D metabolism, FGF23 and mechanical loading we hypothesise that mechanical loading still has positive effects on bone even if vitamin D and Sex hormones are deficient. In this proposal we aim to study the role of phosphate homeostasis and vitamin D and sex hormone metabolism in the response of bone to mechanical loading. We will test the response of bone metabolism to axial tibia loading with either sufficient or deficient vitamin D status. (Soluble) Klotho in bone tissue in combination with FGF23 will be identified with a double staining procedure. Furthermore we will study the interaction with sex hormones because of important changes in these hormones during aging.
MAXIMUS: maximizing muscle recovery after stroke
PI: prof. M.A. Slevin, IRM, United Kingdom; co-PI: prof.dr. G. Kwakkel, MOVE, Netherlands
PhD fellow: Arjun Paudyal
Optimal recovery after stroke is a major target of neurologists and is key to maintaining the best possible quality of life. It is now accepted that carefully controlled exercise (even passive movement in severe stroke cases) undertaken by the patient-particularly during the acute phase (0-3 days)- leads to improvement in recovery. However, neither the mechanisms through which this may occur (e.g. the effects on the brain and the musculature), nor the optimal timings for induction are known. While much research is focussed on attenuating the associated changes in the brain, much less is known about the effects on the muscle. Yet, stroke does have a negative effect on muscle, the most conspicuous one being atrophy and loss of muscle strength. These changes are primarily the result of an, at least transient, denervation of the muscle. During denervation there are early transient changes in the muscle, such as an increased number of satellite cells and denser capillary network, which are conducive for subsequent recovery. If this also applies to muscles affected by stroke then there might be a ‘window-of-opportunity’ where the impact of rehabilitation on the muscle is optimal. Our study seeks to explore the hypertrophic response to an overload stimulus initiated at different moments after stroke, and how this response can be improved by voluntary aerobic exercise. Here, we will use a stroke model (temporary occlusion) of aged rats (to mimic the effects of stroke in aged patients). At different time points after stroke the plantaris muscle in one leg will be subjected to a hypertrophic stimulus. One group of rats will exercise using a rotating wheel whilst another group will remain sedentary. Cognitive and memory testing will be used to define improvement in brain function, whilst after 4 weeks of induction of hypertrophy detailed analysis will be carried out on molecular changes occurring in both brain and muscle tissue. In Amsterdam, patient recovery profiles will be studied in terms of synergism, strength, sensory deficits and upper limb function during the first 6 months post stroke. The results of the study may have serious implications for the treatment of people in the subacute phase after stroke, as it may reveal the importance of the dose of exercise therapy in facilitating muscle and brain recovery.
Understanding hand motor control in healthy aging
Project I: Muscle mechanics and neural control of the aging hand
PI: prof.dr.ir. D.F. Stegeman, MOVE, Netherlands; co-PI: prof. I. Jonkers, K.U. Leuven, Belgium
PhD fellow: Nathalie van Beek
Quality of fine hand motor control decreases in the elderly. Deterioration of handwriting and de-creased stability in other precision tasks, like grasping and fine handicraft, reflect a loss of movement flexibility. A number of factors can be held responsible. Wrist joint mobility can become limited, but also the biomechanical function of individual muscles and their neurophysiological characteristics in the musculosketetal complex may change. Both neural and mechanical muscle and tendon connectivities are essential in the system’s versatility. This project is one of two projects, which have as major objective to increase our understanding of the changing “neuromechanics” of hand motor control with age. The experimental data collected will be used to further develop and tune a hand model by biomechanical constraints and valid muscle activation parameters (project II). This all to increase its quality and validity to allow prediction and understanding phenomena as occur in the aging population. We will first study the biomechanics of the interaction and the connection of muscles and tendon structures with advanced 3-D dynamic ultrasound during various manipulations of finger positions and finger endpoint forces. The question is whether documented age related changes in musculoskeletal mechanical properties contribute to the deterioration of fine control of the fingers.
Effects of home-based training with telemonitoring guidance in low- to moderate-risk patients with ischemic coronary artery disease
PI: prof. L. Vanhees, K.U. Leuven. Belgium; co-PI: dr.ir. H. Degens, IRM, United Kingdom
PhD fellow: Andrea Avila
Cardiovascular diseases are the main cause of death worldwide. Exercise-based cardiac rehabilitation (CR) does improve exercise capacity, reduces the number of hospital admissions and total and cardiovascular mortality in patients with cardiac diseases. Despite these beneficial effects of CR participation remains sub-optimal. Even in those that do participate it is difficult to maintain these training-derived improvements, largely because patients do reduce their activity levels after completion of the rehabilitation period. The main reasons for not attending CR are difficulties to regularly attend sessions at their local hospital and a reluctance to take part in group-based classes. Home-based CR programs circumvene these problems. Compliance and reduction of drop out numbers in home-based programs may be enhanced even further when these programs are combined with the Wireless Body Area Network (WBAN) and remote decision support by medical professionals (hence forward called home-CR). A better compliance and adherence to the programs might result in lower numbers of re-hospitalisation and hence prove to be more cost-effective than on-site rehabilitation programs. The main objective of this study is to investigate whether a 3-month home-CR program with WBAN and remote decision support does indeed result in higher physical fitness, both in the short and longer term, as compared to regular practice in low- to moderate-risk CR patients. Thereto, 90 patients will be randomized to Home-CR, a center-based program or an advice only group (= control group). Assessment will be performed at baseline, immediately and 9 months after completion of the programs and will include in vivo measurements of peak oxygen uptake, physical activity (objective and subjective measurements), muscle strength, endothelial function, health-related quality of life and patient satisfaction. In a subset of patients, a muscle biopsy will be taken to investigate the muscle adaptations in terms of muscle fibre size, fibre type composition, oxidative capacity and capillary supply on the short term. These biopsy data will reveal to what extent the improvements in fitness are a consequence of muscle adaptations, the magnitude of the adaptations to the supervised CR versus advice only and to what extent these adaptations are maintained after completion of the rehabilitation programs.
Does The Osteocyte Lacuna Affect Bone Adaptive Response In Aging?
PI: Prof. dr. ir. H. van Lenthe, K.U. Leuven, Belgium; co-PI: prof.dr. J. Klein-Nulend, MOVE, Netherlands
PhD fellow: Haniyeh Hemmatian
Osteoporosis is by far the most common bone disease, resulting in nearly four million osteoporotic bone fractures in Europe each year. Hence, there a strong socio-economic need to reduce the number of fractures. Low bone mass, the hallmark of osteoporosis, is a consequence of a negative balance in the bone remodeling process. This proposal is aiming at improving our understanding of this age-related bone loss preceding bone fracture. The osteocytes (OCY), the most abundant bone cell type, play a key role in the remodeling process by directing the osteoblast (bone building cells) and the osteoclasts (bone removing cells). Supported by recent evidence that OCYs can modify their micro-environment, we hypothesize that changes in the OCY lacunar morphology lead to changes in the stress conditions experienced by the OCY, giving rise to a modified response to mechanical loading.
We will test this hypothesis on bones from the lower legs of young and old mice that will be subjected to mechanical loading. We will provide quantitative data on OCY shape, size, and number on OCY activity, and how these relate to local mechanical stresses.
Specifically, the following objectives will be addressed:
1: quantify load-induced changes in OCY morphology
2: quantify load-induced changes in OCY activity
3: relate local bone mechanical strain to local OCY morphology and activity
This will allow assessing whether changes to the osteocyte lacuna are related to the reduced bone adaptive response as seen with aging. We expect that this will lead to a better understanding on the role of OCY lacuna on functional bone adaptation. We also expect that by assessing the role of the lacunar morphology and number in mice we will come to a better understanding of the same remodeling events in humans, thereby elucidating a pathway in the etiology of osteoporosis. Given the crucial importance of osteocytes in maintaining a “good bone health” (i.e., a proper resistance against bone fracture), greater knowledge of the mechanisms that govern the adaptive response of osteocytes to mechanical stimuli may lead to the development of new strategies towards improving bone quality and fracture prevention.
Optimising virtual reality interventions for improving balance and preventing falls in different populations of elderly
PI: Prof. dr. S.M.P. Verschueren, K.U. Leuven, Belgium; co-PI: prof.dr. J.H. van Dieën, MOVE, Netherlands
PhD fellow: Aijse de Vries
Virtual reality (VR) balance training may have advantages over regular exercise training as it combines motor and cognitive training, provides immediate feedback of performance, and creates an environment of enjoyment through gaming which enhances attention and motivation of the participants. VR training might thus be a useful rehabilitation tool to exercise balance and reduce the risk of falls in old age. However, the small number of available studies on the effect of VR balance training have yielded conflicting results. One explanation for this inconsistency might be that, with commercially available games, it remains uncertain if and to what extent the movements that are actually performed as well as the intensity and level of difficulty of the games are optimal for improving balance. In this context, the first aim of the present project is to assess the motor learning and the motor performance of subjects performing virtual reality balance games of the Stable system (Motek medical). Second, based on an analysis of the performance of subjects, and taking into account some best practice recommendations for (balance) training, the games will be adjusted to optimize the balance challenge. The final aim is to assess the effects of long term training with these optimised virtual reality games on balance and fall risk in an RCT in older individuals with a history of falls. Ultimately, the availability of effective virtual reality games to improve balance and reduce falls might contribute to novel rehabilitation strategies like tele-rehabilitation, a potentially fruitful and cost-effective approach to fall prevention.
PROJECTS STARTED IN 2012
Watch out! Gait adaptability in older adults with low and high executive function
PI: prof.dr. P.J. Beek, MOVE, Netherlands co-PI (mobility period): prof.dr. J. Duysens, KULeuven, Belgium
PhD fellow: Masood Mazaheri
Fall incidents in older adults frequently result from trips, slips, and misplaced steps. Such gait-related falls cause serious morbidity and mobility problems. Hence, it is relevant to gain more insight in the factors underlying age-related gait deterioration, which becomes particularly apparent when walking on complex terrains. In this context, age-related changes in the visual control of gait appear to play an important role. In addition, gait deterioration in elderly is associated with decreased executive function (EF). However, it is unclear exactly how decreased EF influences gait control.
We propose that, when walking on visually complex terrains, low EF induces deteriorated visuomotor control, which is associated with increased attentional demands. This is examined by determining how aging and variations in EF relate to 1) the attentional demands of both planning and execution of gait control, and 2) vision-based gait control and the associated attentional demands of visually-guided stepping.
To this end, performance of young adults is compared to that of healthy elderly with either high or low levels of EF. Participants walk on an instrumented treadmill with adjustable visual context, while
attentional demands are assessed using a probe reaction time task. Both the visual context and the gaze strategies (registered using a gaze tracking system) are manipulated to address the relations between EF, visual gait control, and attentional demands.
The results will provide vital information about the value of complex walking environments for the design and implementation of diagnostic tools and training interventions.
Understanding muscle and bone anabolic resistance in ageing: is ER stress involved?
PI: prof.dr. P. Hespel, KULeuven, Belgium, co-PI (mobility period): prof.dr. J. Klein-Nulend, MOVE, Netherlands
PhD fellow: Sreeda Chalil
The number of ageing people is increasing dramatically in Europe. Ageing is associated with a loss of muscle and bone mass, which in turn leads to a series of side effects (decreased strength and insulin sensitivity, increased risk of bone fractures, falls and mortality, etc.). These effects not only decrease overall health, but also reduce mobility and increase the dependency on others during activities of daily life. It is therefore essential to develop strategies aimed at limiting the detrimental effects of ageing.
One major cause of the reduction in muscle mass with ageing is the so-called anabolic resistance, which is defined as a blunted response to hypertrophic stimuli such as exercise and nutrition. Furthermore, it has recently been shown that anabolic resistance can be partially due to a disturbance in the endoplasmic reticulum (ER), an intracellular membrane network implicated in protein folding. We thus hypothesize that ER stress could be involved in the reduced response to anabolic stimuli, and as such, the loss of muscle mass in ageing people. The implication of the ER stress in the loss of muscle mass will be examined in vitro and in elderly humans.
As mentioned previously, skeletal muscle is not the only tissue that is affected by ageing. The skeletal system also shows signs of deterioration in the form of bone loss with damage to the microarchitecture of the bone (osteoporosis). Osteoporosis in turn, leads to an increased risk of bone fractures (e.g. hip fractures) and these fractures are the main reason for the loss of self-reliance in this population. One of the main determinants of osteoporosis is the increase in bone remodelling rate, with an imbalance between bone formation and bone resorption, partly resulting from a decline in the osteogenic response with aging. Since there are similarities between the molecular pathways responsible for bone and muscle metabolism, we hypothesize that ER stress also could play a role in the decreased anabolic response in bone tissue.
We expect that the results obtained in this project will contribute to the identification of novel pharmacological targets and a better understanding of how modification of nutritional patterns could help to counterbalance, or reverse, the deleterious effects of sarcopenia and osteoporosis.
Mechanisms underlying the changes in muscle quality and quantity with ageing
PI: prof.dr. D.A. Jones, IRM, UK, co-PI (mobility period): prof.dr. A. de Haan, MOVE, Netherlands
PhD fellow: Jorgelina Ramos
The decrease in muscle strength with ageing is associated with two main changes, a decrease in muscle quantity as a result of both loss and atrophy of fibres and, secondly, a change in muscle quality evident as a change in speed of contraction and a decrease in the force generated per unit cross sectional area of muscle (specific force). While the contractile slowing and fibre atrophy have received most attention in ageing research these constitute only one aspect of the problem and the decrease in specific force and the loss of fibres and of motor units as a consequence of motoneuron death, have been largely ignored: we suggest these latter factors make a substantial contribution to the loss of muscle function. In addition, motoneuron loss will impair motor control and exacerbate the problems associated with the loss of muscle function.
The first phase of the proposed study will be to determine the relative contributions of fibre loss and decrease in specific force to the overall decline of muscle function while the second phase will examine the possible causes of motoneuron death and the decrease in specific force. Two possible causes of motoneuron death will be considered, a decrease in growth factors expressed in muscle that are required to sustain motoneurons and an accumulation of DNA damage that has also been implicated in motoneuron disease. The investigation of changes in specific force will concentrate on the hitherto unexplained observation that while isometric and concentric force decline with age, there is a preservation of force sustained as the muscle is stretched. Using skinned fibre preparations we will examine the hypothesis that aged muscle has an altered sensitivity to inorganic phosphate which would explain the relative preservation of eccentric strength.
There are no immediate practical applications of the proposed study but if motoneuron death is found to be an important factor in the decline of muscle function with age it will substantially change the emphasis of the search for palliative interventions away from the muscle fibres to the motoneurons. Likewise, if the phosphate hypothesis is substantiated it would direct future research to finding ways in which intracellular phosphate might be manipulated.
Quantfying aberrant mechanical loading in medial knee osteoarthritis
PI: prof.dr. I. Jonkers, K.U. Leuven, Belgium; co-PI (mobility period): prof.dr. C. Maganaris, IRM, UK
PhD fellow: Susana Ferreira Meireles
Knee joint loading has been identified as potential risk factor affecting development and progression of knee osteoarthritis (OA). The precise relationships between OA and mechanical loading of the knee joint are as yet unknown as data on knee joint loading are lacking andcondition-specific models relating joint loading and local cartilage strains are missing.
The aim of this project is (1) to quantify mechanical loading of the knee during functional activities (gait and stair negotiation) in terms of knee contact forces, and to evaluate differences in mechanical loading with OA involvement using a cross-sectional study design, and (2) to evaluate the effect of these differences on tibiofemoral cartilage loading. We hypothesize that in subjects with different levels of OA involvement, the knee joint loading is significantly altered due to the combined effect of aberrant movement dynamics, muscle coordination and joint geometry as well as local alterations in tissue properties of the knee structures, all adversely affecting the cartilage strains in the medial compartment.
A first objective customizes an existing workflow combining integrated 3D motion capture with individualized dynamic simulations of motion using musculoskeletal models to calculate knee joint loading during functional activities. Specific emphasis is on appropriate incorporation of the knee joint kinematics and altered muscle activation around the knee. Using this workflow we quantify knee joint contact forces during functional activities, more specific gait and stair negotiation, in a cohort of early stage medial OA patients (20 subjects, Kellgren Lawrence ≥1 and ≤2), a cohort of end stage medial OA patients (20 subjects, Kellgren Lawrence ≥ 3) as well as a group of control subjects (20 subjects)
The second objective is to evaluate the effect of these calculated changes in contact forces on cartilage strains using a generic FE model of the tibiofemoral joint. A sensitivity analysis will separately evaluate the effect of the calculated contact forces, cartilage material properties and geometry on the calculated strains in the medial compartment of the tibiofemoral joint.
Successful completion of the project will provide evidence of altered mechanical loading in the knees of patients with knee OA and is a first step toward detailed monitoring of the mechanical consequences of the disease.
PROSPER: Longitudinal PatteRning Of changes in Synergistic-basEd movement during stroke Recovery.
PI: prof.dr. G. Kwakkel, MOVE, Netherlands; co-PI (mobility period): prof.dr. A. Nieuwboer, K.U. Leuven, Belgium
PhD fellow: Mojdeh Khorrami
The processes underlying motor recovery after stroke are largely unknown. Motor recovery can occur in different phases, typically starting with early, synergy-based movement patterns (e.g. flexor/extensor synergies) to later, fully dissociated and/or independent movement. The origin of these early stage synergies as well as the ’spontaneous’ recovery in the first weeks post-stroke are poorly understood. Most probably recovery involves different mechanisms including salvation of penumbral tissue and elevation of diaschisis (or shock) enhanced with homeostatic neuroplasticity due to an up-regulation of growth promoting genes early after stroke. It is believed that (anti-) Hebbian learning processes during this critical, early time window may enhance spike-time dependent neuroplasticity by long-term potentiation (LPT) and depression (LTD). In addition, studies on transcranial Direct Current Stimulation (tDCS) provided evidence that such synapse-based learning in the affected hemisphere can alter neural circuits of both the affected and non-affected hemispheres. The present proposal aims for three key targets in stroke rehabilitation: (i) We will investigate the immediate effects of anodal and cathodal tDCS on upper and lower limb motor function (e.g. dexterity and gait/balance tasks) in terms of movement synergies, kinematics and brain functional connectivity. (ii) In 40 (sub)acute stroke patients we will study if a three-week repetitive administration of anodal and cathodal bihemispheric tDCS or sham tDCS combined with a modified Constraint Induced Movement Therapy (mCIMT) protocol or Postural Feedback Training (PFT) allows for modulating the natural pattern of motor recovery. (iii) We will look for causal relationships between improvement in synergy-based movements as a reflection of true neurological recovery and recovery of the upper and lower limb function and activity during the first six months post stroke. We expect that 1) a single session of active tDCS will show immediate changes within cortical networks of sensorimotor areas accompanied by improvements in motor performance, 2) intervention paired tDCS-CIMT and tDCS-PFT training will augment motor performance and outcome of body functions and activities when compared to an equally dosed training with sham-stimulation.
Psycho-physical mechanisms of immobilisation
PI: prof.dr. I. Loram, IRM, UK; co-PI (mobility period): prof.dr. P. Beek, MOVE, Netherlands
PhD fellow: Jonathan de Melker Worms
Mobility loss in ageing can result from a combination of physical and psychological factors. In one common scenario, people lose confidence in their ability to balance, perhaps following a fall, and develop fear of falling. They become unable to move to their best ability. Even though they retain capability generally such as good cognition, they underperform with respect to balance and movement. Our hypothesis is that fear of falling and the associated immobilisation (task avoidance, muscle tensing), is an internal, closed loop feedback process in which perception of the challenging task and the motor coordination effecting the response mutually sustain and reinforce each other. The solution suggested by this approach is to identify the psychological and motor coordination elements of the feedback process and apply external negative feedback to reduce their effect.
Using novel techniques, this project will provide, for the first time, a unique characterisation of the muscle coordination and associated changes in perception, attention and reactivity associated with fear of falling. The applicant will use a proven paradigm for inducing fear of falling in young people – namely a 7m long, 22cm wide, 4m high walkway and cliff. Using newly develop ultrasound analysis to reveal contraction in the deep neck and back muscles, together with motion analysis and EMG, the pattern and timing of the muscle coordination of fear will be established. Using psychological techniques, this will be related temporally to changes in perception, attention and reactivity. The characterisation of fear of falling from the “young person model” will be compared with elderly at a reduced height of 1m. The feasibility of targeting the motor and perceptual processes using external feedback will be investigated.
Through the application of new muscle recording techniques to provide previously unobtainable information, and through the mechanistic rationale, this is a project of ground breaking scientific quality. Fear of falling and the psycho-physical process of immobilisation is studied at the integrative level. The mechanistic approach provides the foundation for an intervention that can effectively restore balance confidence and mobility in the elderly where this has been lost following a fall or some other trauma.
The role of lower-limb biomechanics and energy cost in walking difficulties experienced by older people with Type 2 diabetes
PI: dr. N. Reeves, IRM, UK; co-PI (mobility period): prof.dr. S. Verschueren, K.U. Leuven, Belgium
PhD fellow: Milos Petrovic
People with type 2 diabetes engage in less physical activity and walk less compared to controls, which is detrimental for maintaining glycaemic control and general management of the diabetic condition. Also, self-selected walking speed is much slower and maximum walking speed substantially lower in people with diabetes. We hypothesise that altered lower-limb biomechanics and a higher energy cost for walking could be possible explanations as to why people with diabetes walk less, display slower self-selected walking speeds and appear to display ‘inefficiencies’ when walking faster. Also, the stiffening of major locomotor tendons due to diabetes will reduce their efficiency for storing and releasing elastic energy and further increase the energy cost of walking. The above hypotheses will be tested in the laboratory in diabetes patients and matched-controls by firstly examining the biomechanics of walking. The external moment arm and the effective mechanical advantage around the ankle will be examined from kinetic and kinematic data. This data will then be linked with realtime imaging of the Achilles tendon to directly examine utilisation of elastic energy during walking across a range of velocities. The oxygen cost of walking at different velocities will be examined using an online measurement system during walking on a treadmill. The mechanical properties of the Achilles tendon will be determined to quantify any difference in stiffness caused by diabetes that may impact upon walking. In KU Leuven, a detailed kinematic analysis of the diabetic foot will be undertaken using a multi-segment model. This study will examine the mechanics of the diabetic foot and will investigate how this may influence the energy requirements from the muscles surrounding the ankle, contributing to the overall goal of determining the influence of biomechanics and energy cost on walking difficulties experienced by people with type 2 diabetes.
Determinants of falls risk in older orthopaedic patients
PI: dr. M. Pijnappels, MOVE, Netherlands; co-PI (mobility period): prof.dr. S. Verschueren, K.U. Leuven, Belgium
PhD fellow: Mina Arvin
The ageing population faces an increased risk of falling and of the fall consequences. It is estimated that about 33% of the elderly fall each year and falls often result in injuries, disability and inactivity. The strongest risk factors of falls in elderly have directly or indirectly been associated to mobility. These factors include previous falls, strength impairments, gait impairments, balance impairments and medication. A specific population in which many of the falls risk factors are present are older orthopaedic patients. Visits of these patients to orthopaedic outpatient departments are often the direct or indirect result of a fall. Another part of the population of orthopaedic patients that is at risk for falling are patients with osteoarthritis (OA). These patients often have to undergo a (partial) replacement of their hip or knee joint, nevertheless remaining highly at risk for falling. Insight in fundamental determinants of falls risk in elderly orthopaedic patients is lacking but necessary for developing and implementing specific interventions for this diverse, but highly fall prone population.
The overall aim of the proposed research project is to identify specific determinants of (recurrent) falls in older orthopaedic patients, including patients with knee OA, before and after orthopaedic surgery, either due to fall-related injuries or to lower limb joint replacements. In a one-year prospective study, differences in retrospective and prospective falls risk and its associations with (determinants of) strength, balance and gait are studied between 1) patients that receive surgery to either the lower extremities or the upper extremities because of a fall, 2) patients with osteoarthritis that receive either a total hip arthroplasty or a total knee arthroplasty, 3) patients with various levels of severity of osteoarthritis of the knee, and 4) patients that receive surgery at the hip either because of osteoarthritis or because of a fall. Identification of such determinants is necessary to increase mobility and reduce falls risk after surgical interventions and the following hospital stay and rehabilitation period and to increase quality of life and the ability to live independently for each of these subpopulations.
Aging and brain plasticity: alterations in brain structure, function and connectivity and their implications for motor coordination
PI: prof.dr. S. Swinnen, K.U. Leuven, Belgium; co-PI (mobility period): dr. A. Daffertshofer, MOVE, Netherlands
PhD fellow: Laura Milena Rueda Delgado
The aging population poses unprecedented challenges for society. We aim to advance our understanding of age-related changes in the brain and how these impact upon movement control. Changes in motor functioning are constrained or maybe even caused by functional, structural, and connectivity changes in the normally aging brain. We will use an array of state-of-the-art neuroimaging techniques that allow us to assess whole brain activity and combine them with behavioral paradigms to study complex motor tasks, in particular bimanual coordination. Even though we will study the whole brain, the corpus callosum is central in this project because it is a critical structure in interhemispheric interactions and brain organization. Our aims are twofold. First, we will determine how lifespan alterations in complex motor tasks (bimanual coordination and response switching) can be accounted for by functional (brain activation), structural (white and grey matter) and connectivity changes in young versus old groups (Phase 1). Second, we will explore experience-dependent neuroplasticity via the study of age-related alterations in brain structure, function, and connectivity as a result of intensive training (Phase 2). This project will reveal new insights into age-related alterations in the brain and its implications for motor control and plasticity, an endeavor of high socio-economic relevance.
PROJECTS STARTED IN 2011
Impaired muscle function and hypertrophy at old age: due to oxidative stress and/or low-level chronic systemic inflammation?
PI: dr. ir. H. Degens IRM, UK; co-PI (mobility period):prof.dr. A. de Haan, MOVE, Netherlands
PhD fellow: Sam Ballak
Age-related muscle wasting (sarcopaenia) and weakness ultimately leads to a dependent lifestyle. Although myofibre loss, atrophy and reduced myofibre function contribute to the age-related decline in muscle function, the relative contribution of each of these changes to reduced muscle function is unknown. Also the response to resistance exercise training (hypertrophy) is attenuated and the elderly often suffers from an earlier onset of fatigue. Diminished mitochondrial function may play a key role in all these impairments.
The overall aim of this study is to examine the causes of impaired muscle function and attenuated hypertrophic response in old age. The objectives are to 1) quantify the relative contribution of myofibre loss, fibre atrophy and impaired fibre function to sarcopaenia and muscle weakness, 2) determine the relationship between reduced mitochondrial function with mechanical efficiency, muscle fatigue resistance and myofibre function, 3) determine the extent to which attenuated muscle hypertrophy in response to overload is explicable by quantitative and qualitative changes to myofibres and mitochondria and 4) determine to what extent anti-oxidant treatment can rescue some of the reduction of myofibre function and hypertrophic response at old age.
Mouse plantaris muscle function will be determined in vivo. Single fibre function will be studied in vitro. We will overload one plantaris muscle and the contra-lateral muscle will be used as an internal control. We hypothesise that part of the decline in fibre function, fatigue resistance and hypertrophy is caused by impaired mitochondrial function. Therefore, we will assess to what extent changes in the oxygen flux:work ratio in in vitro muscle bundles correlate with the decline in fatigue resistance, myofibre function and hypertrophy at old age. If mitochondrial dysfunction impairs muscle function and hypertrophy via oxidative stress, then muscle impairments should be ameliorated, at least to some extent, by treatment with an anti-inflammatory anti-oxidant, such as resveratrol.
The outcome of this work identifies the main contributor to sarcopaenia and the age-related muscle dysfunction. At the same time it provides insight into what limits the improvements in muscle function. This will inform the design of therapeutic interventions to reduce the age-related decline in muscle function.
The ability of older adults to suppress unwanted lower limb reactions to daily life perturbations
PI: prof.dr. J. Duysens, KU Leuven, Belgium; co-PI (mobility period): dr. M. Pijnappels, MOVE, Netherlands
PhD fellow: Zrinka Potocanac
To move appropriately in daily life, it is essential to suppress inappropriate movements. For example, during walking one has to suppress to step on a suddenly perceived slippery patch in order to avoid falling. Presumably, such reactions require some form of response (or motor) inhibition of a prepared or cyclic action. Such inhibition is especially important for leg movements in the elderly. Indeed many falls in this group are related to the inability to react properly to obstacles that appear or are noticed suddenly. Still most studies on inhibition have focused on upper extremity movements or verbal responses. There are some indications that suppression of upper limb movements are reflected in suppression of lower leg muscle activity but so far there have been no systematic attempts at studying response suppression in an ambulatory context. In the present project, the primary aim is to study response inhibition in the legs of elderly in balance threatening, daily life situations (e.g., avoiding stepping on a given area – i.e. a snail – which is suddenly perceived after tripping or during a corrective step).
For this purpose, elderly will first be tested with the classic verbal tests for response inhibition, both while sitting and during walking, and the results will be compared to those of young adults. These data will then be related to those of various experiments, imitating commonly encountered situations. Elderly will walk on a treadmill while being asked to avoid suddenly appearing patches of light. In other experiments the potential to avoid stepping on a given area after tripping (over ground walking), or after being perturbed on a platform, will be explored and trained. Measurements of force (angular momentum), movement and EMG will be used. Preference will be given to elderly subjects who are well documented in terms of brain structures (Diffusion Tensor Imaging, a magnetic resonance imaging technique to study white matter). This allows comparing structural deficits with deficiencies in response inhibition. The results of this project will provide insight into the feasibility for training of inhibitory responses in older people, which could lead to a reduction in falls.
Does Current Anti-Hypertensive Treatment Interfere With The Promotion Of Fitness By Physical Activity?
PI: prof.dr. M. Flueck IRM, UK; co-PI (mobility period): prof.dr. A. de Haan, MOVE, Netherlands
PhD fellow: Sander van Ginkel
Metabolic fitness is a critical determinant for mobility and quality of life in the elderly and predictor of morbidity and frailty 1. High blood pressure (hypertension) indicates the deterioration of the set points of metabolic fitness. The risk to develop hypertension and associated metabolic syndromes increases with age 2. Consequently hypertension is a major target of the current pharmacological treatments producing yearly expenses in the order of 100s of million Euros in middle-sized European countries alone.
Our proposal aims to address the side effects of the most commonly used class of anti-hypertensive drugs, which target the vasoconstrictory peptide angiotensin 2. This study focus is motivated by the experimental evidence showing that angiotensin 2 is necessary for growth of capillaries 3 and our observations that the reduction of angiotensin 2 production due to genetical or pharmacological inhibition of angiotensin converting enzyme (ACE) blunts the expression response which activates capillary growth in exercised muscle. The results support the working hypothesis that serum angiotensin 2 induces growth (angiogenesis) of perfused capillaries in working muscle by activating endothelial cells within the inner wall of blood vessels. This mechanism is not obvious in the resting state, when the perfusion of skeletal muscle is low because angiotensin 2 mainly exerts its vasoconstrictory function 4 and can not enter the capillary bed. This activity dependent mechanism has not been considered in pharmacological studies. It therefore appears that angiotensin 2 directed pharmacology diminishes the potent capacity of physical activity to enhance muscle’s capillarity, which is a critical regulator of insulin-sensitivity, metabolic fitness and systemic blood pressure.
This hypothesis will be tested with a pharmaco-genetic approach in a population of healthy individuals. Our human study will comprise 4 parts divided in 1) the characterisation of the intensity-dependence of angiotensin 2 concentration in serum, 2) the recruitment and characterisation of subjects according to genotype and fitness, 3) an invasive exercise-intervention under a supervised pharmacological treatment to inhibit angiotensin 2 production, 4) an analytic part that characterises the effect of the ‘genetic and pharmacological inhibition of angiotensin 2 production’ on the promotion of capillary growth by exercise.
The etiology of generalized osteoporosis in rheumatoid arthritis
PI: prof.dr. J. Klein-Nulend, MOVE, Netherlands; co-PI (mobiliy period): prof.dr. F. Luyten, KU Leuven, Belgium
PhD fellow: Janak Lal Pathak
Inflammatory diseases are often associated with a loss of bone mass throughout the skeleton (generalized osteoporosis). This bone loss is associated with an increased incidence of vertebral and hip fractures, which results in morbidity, mobility loss and can even result in death. In patients with Rheumatoid Arthritis (RA), inflammatory mediators produced by cells around inflamed joints are known to contribute to bone loss around the affected joints. The same inflammatory mediators may also contribute to the etiology of generalized osteoporosis, since these mediators are able to enter the bloodstream thereby reaching bone cells in remote areas.
We hypothesize that circulating inflammatory mediators are the main causative factor for the emergence of generalized osteoporosis in patients with RA. Based on this hypothesis, we will identify and quantify an extensive number of well-known and less well-known inflammatory mediators in serum of a well defined group of early RA patients, healthy age and gender matched controls, and RA patients in remission, using state-of-the-art protein array techniques. We will also investigate which cell type, i.e. the bone forming osteoblast, the osteoblast precursor, the bone resorbing osteoclast, and/or the “bone orchestrator cell”, the osteocyte, is affected most strongly by serum from patients with active RA, which contains a cocktail of inflammatory mediators. The effect of RA or control serum on the function of the four different cell types is tested in vitro, using the unique expertise of the research groups involved regarding human osteoblast precursor, osteoblast, osteoclast, and osteocyte biology. By correlating the effect of serum on bone cell function with changes in cytokine expression in serum of patients with RA, we expect to identify a combination of inflammatory mediators that most strongly affect bone cell function.
We expect that the proposed research will identify inflammatory mediators that are crucial for the etiology of generalized osteoporosis in patients with inflammatory diseases. Our results can likely be extended to localized bone loss around inflamed joints in RA. The results of this research will offer multiple opportunities for the development of new therapeutic agents to prevent inflammation associated generalized osteoporosis, thereby preventing mobility loss with aging.
Future Functional Status in Osteoarthritis of the Knee: Impact of Neuromuscular, Psychological and Clinical Factors (NPC-study)
PI: prof.dr. W. Lems, MOVE, Netherlands; co-PI (mobility period): prof.dr. S. Verschueren, KU Leuven, Belgium
PhD fellow: Diana Sanchez Ramirez
Background: Osteoarthritis (OA) of knee is characterized by considerable between-patient variation in the course of functional status: some patients seem to remain stable or to even improve, whereas others deteriorate. Understanding the mechanisms explaining future functional status of OA patients is therefore highly relevant.
Aim: The overall aim of the present study is to enhance our understanding of the mechanisms explaining future functional status in knee OA. Specific objectives are: (1) to evaluate whether neuromuscular factors explain future functional status in knee OA; (2) to evaluate whether pain-induced avoidance of activity explains future functional status in knee OA; (3) to synthesize information on neuromuscular, psychological, and clinical factors into clinical prediction rules for functional recovery or functional decline in knee OA.
Method: Prospective longitudinal study among patients with established knee OA in the Amsterdam Osteoarthritis Cohort (AOC), which is a unique and large cohort combining clinical measurements with measurements of neuromuscular factors, psychological factors and functional status. Measurements are conducted at baseline and 2 years follow-up. Measurements include: radiographs of the joint, comorbidiy, sociodemographic characteristics, muscle strength (quadriceps, hamstrings), laxity of the knee joint, proprioception, negative affect (anxiety, depression), avoidance of activity, functional status (pain, physical functioning, Get Up and Go (GUG) test, timed stair-climbing test). Multivariable linear regression analysis is used to test specific hypotheses related to objectives 1 and 2. The prediction rules are based on the results of these analyses and evaluated using the Area Under the Receiver Operating Characteristic curve (AUC).
Expected results: (i) Conclusions on the validity of neuromuscular factors as an explanation for future functional status in knee OA; conclusions on the validity of avoidance of activity as an explanation for future functional status in knee OA; and clinical prediction rules for functional decline or recovery in knee OA.
Identification of risk factors associated with the progression of knee-osteoarthritis: a prospective longitudinal study
PI: prof.dr. F. Luyten, KU Leuven, Belgium; co-PI (mobility period): prof.dr. J. van Dieën, MOVE, Netherlands
PhD fellow: Armaghan Mahmoudian
OA is a chronic degenerative disease with the knee as most affected joint. Indeed, more than 10 % of the population above 60 years has osteoarthritis (OA) of the knee. However, only about 15 % of these individuals will progress towards an end-stage process with important disability, and thus a need for prosthetic knee replacement. Identifying prospectively the “progressors” is thus a key issue in OA, because these patients could benefit from more intense disease management than patients with typical rather age-related intermittent osteoarthritic complaints. The aim of this project is therefore to further identify neuromuscular, biomechanical (structural) and symptomatic risk factors for progression of knee osteoarthritis and to determine their mutual relationship and relative importance in a 2-year prospective longitudinal study.
One hundred and twenty subjects (40 control subjects, 40 patients with symptomatic knee OA, 40 patients with symptomatic and radiographic knee OA) have been measured at baseline in a previous cross-sectional study and will be measured at one and two years follow-up in the present study. The presence of potential (neuromuscular, biomechanical, genetic and clinical) risk factors at baseline will be associated with the changes in severity of osteoarthritis (clinical- structural) over this period.
The outcome of this project is to identify critical factors for progression, and set the stage for the design of a new prospective study to validate these findings. Ultimately, the development of optimized management strategies based on the major and modifiable risk factors for progression of knee osteoarthritis may lead to a more successful outcome in knee osteoarthritis.
Knee osteoarthritis and stair negotiation
PI: prof.dr. C. Maganaris, IRM, UK; co-PI (mobility period): prof.dr. S. Verschueren, KU Leuven, Belgium
PhD fellow: Katerina Doslikova
Knee osteoarthritis (OA) is one of the most prevalent forms of OA in old age and is associated with pain and loss of mobility. It is widely recognized that the knee adduction moment that is developed in the stance phase of walking is implicated in the initiation/progression of the disease. Stair negotiation is more challenging than walking and it often results in falls in old age. In addition, walking on stairs causes greater knee adduction moments than walking on flat, and negotiating stairs daily may therefore cause knee OA to progress faster; hence, it is important that effective interventions are established to minimize the deteriorating effect of the daily use of stairs in knee OA patients and reduce the risk of accidents on stairs. To achieve this aim, we suggest four studies. Study 1 will establish the biomechanical strategies that knee OA patients use to negotiate stairs and how these differ from the strategies that healthy age-matched individuals exhibit. Studies 2 and 3 will investigate the effectiveness of corrective footwear and knee bracings and modified gait strategies for reducing the knee adduction moment during stepping up and down. Finally, study 4 will examine the effectiveness of an exercise-training program of the hip abductors and knee flexors for unloading the OA knee on stairs.
The contribution of motor switching to freezing of gait in Parkinson’s disease: differential effects of complex gait and postural demands in freezers and non-freezers
PI: prof.dr. A. Nieuwboer, KU Leuven, Belgium; co-PI (mobility period): prof.dr. G. Kwakkel, MOVE, Netherlands
PhD fellow: Farshid Mohammadi
Freezing of gait (FOG) is one of the most debilitating problems in Parkinson’s disease (PD). FOG is known to occur in situations, which pose environmental constraints or require elevated attention, suggesting that freezers may have a cognitive profile which is different from non-freezers and healthy older people. It is also possible that freezers face an episodically induced cognitive or visuomotor deficit, triggered by specific circumstances, which impacts upon the motor system. The most likely cognitive trigger is a deficiency of task-switching and response selection under conflict. Here, we propose to test the assumption that highly integrated motor and cognitive functions of the basal ganglia, which underlie action selection, are differentially affected in patients with FOG compared with those without FOG and older people. Hence, the current proposal offers a cluster of 3 complementary studies designed to study the executive components of FOG. Study 1 and 2 will be investigating the effects of task-switching and how this modulates the regularity of the walking pattern and the adequacy of balance performance. Study 3 focuses on the effects of visual stimuli and a visuomotor switching task on gait modulation and the impact of medication on this process.
Correlation analysis between cognitive and motor tests in combination with the outcomes of the experimental manipulations will allow unraveling of the interplay between motor and cognitive systems in neurodegenerative disease. Also, the symmetry of the proposed experiments will facilitate a better understanding of motor and brain function underlying FOG. Therefore, this research proposal is anticipated to have direct benefits for science as well as health care by focusing on a large clinical population suffering from substantial immobility, falling and reduced quality of life as a result of FOG.
Dynamic balance assessment and training in older adults based on centre of mass tracking performance
PI: prof.dr. J van Dieën, MOVE, Netherlands; co-PI (mobility period): prof.dr. S. Verschueren, KU Leuven, Belgium
PhD fellow: Eduardo Cofré Lizama
Impaired balance control is an important risk factor for falls in the elderly and balance training has been shown to be effective in preventing falls. It is likely that effectiveness can be improved by specifically targeting individuals with increased fall risk due to impaired balance. However, conventional, static methods of testing balance performance have a low sensitivity in predicting fall risk, probably because most falls occur in dynamic tasks such as gait. The first aim of the present project, therefore, is to develop a dynamic method to assess balance performance.
One of the main challenges in training for the elderly is to achieve that individuals continue training to retain effects. Our second aim therefore is to develop and test a training method, suitable for training in the home situation, encompassing feedback to the participant and trainer as well as a game element to enhance motivation and compliance. This training method will be closely integrated with the assessment method.
Assessment and training of balance will be based on tracking tasks performed with the body centre of mass (CoM). For assessment, the bandwidth over which the individual can track a pseudo-randomly moving target with the CoM at a given amplitude in the medio-lateral direction will be determined. This approach will in the current project be used to assess balancing performance, but will in the future also allow determination of limiting factors in balance control. Tracking performance will be correlated to conventional balance measures (e.g. Berg Balance scale) and to gait stability in perturbed and unperturbed treadmill walking and will be related to age and fall history.
For training, both predictable (e.g. moving through a maze) and pseudo-random CoM trajectories will be imposed in the form of games. This allows feedback of performance (and compliance) to the participant and the trainer as well as a systematic increase in the level of difficulty. We will assess the short-term outcomes of the training program in a group of elderly with balance impairments in terms of compliance, balance performance, gait stability, and balance confidence.