Projects to start in 2015

Project 1
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

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.

Project 2
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

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).

Project 3
Interplay of genetic and epi-genetic markers of sarcopenia
PI: prof.dr. Martine Thomis , KU Leuven, Belgium: co-PI: Dr Christopher Morse, MMU, UK

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.

Project 4
Mechanics and energetics of walking in old and young adults
PI: dr M. Bobbert, MOVE, Netherlands; co-PI: dr I. Jonker, KU Leuven, Belgium

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.

Project 5
The genetics of sarcopenia
PI: dr C. Morse, MMU, UK; prof. dr M. Thomis, KU Leuven, Belgium

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.