Normal age-related muscle loss or sarcopenia, affects over 20% of 60-70 year olds rising to 50% in over 75s, leading to muscle function decline and compromising the health status and quality of life of the elderly. There is now increasing recognition of the serious healthcare consequences and attention is firmly focused on this as an important area of future research into ageing. Different aspects of sarcopenia are investigated by researchers at Aberdeen as described below.
Research by Dr. Henning Wackerhage and colleagues in this area is focused on satellite cells, the major resident stem cells of skeletal muscle.
Skeletal muscle has an enormous regenerative capacity which is largely due to satellite cells. These cells are wedged in between the plasmalemma (muscle fibre membrane) and the basal lamina which is a mesh of stringy proteins that surrounds muscle fibres (Figure 1A). Satellite cells are normally quiescent but they become activated and proliferate in response to muscle injury or certain types of exercise. Satellite cells then either self-renew to ensure an ongoing population of satellite cells or differentiate to repair muscle or to donate nuclei to hypertrophying muscle fibres.
Figure 1: (A). satellite cell in the tibialis anterior muscle visualised using electron microscopy (scale bar 2 µm). Note the large nucleus and the paucity of cytoplasm. (B). Activated satellite cells as judged by the presence of MyoD protein after 48 h of suspension culture. (C). Yap is highly expressed in activated satellite cells. The muscle fibre can be seen below (B,C scale bar 50 µm).
We have studied the Hippo pathway member Yap in satellite cells and found that Yap is highly expressed in activated satellite cells (Figure 1B,C). High Yap activity promotes C2C12 myoblast (Watt et al., 2010) and satellite cell proliferation but prevents differentiation (Judson et al. Journal of Cell Science, in press) and this can potentially be exploited to either expand satellite cells within the body or in vitro prior to grafting.
Sarcopenia is caused by many factors including a loss of motor neurones and muscle fibres, anabolic resistance, and a reduced number of satellite cells. Comparing sarcopenic (Figure 2B) to young men (Figure 2A) we have tested that the potent muscle growth inhibitor myostatin and related proteins are changed in the serum of sarcopenic men. Our results show that this is not the case.
Figure 2: (A) MRI image of the mid thigh of a young (18-25 years) and (B) sarcopenic (> 65 years) male. The cross sectional area (CSA) of the thigh muscles is shown as a red, dotted line. Note the much reduced CSA and the fat infiltration in the sarcopenic muscle.
The main research in Dr. Stuart Gray's group is aimed at uncovering the mechanisms underlying sarcopenia and the most effective methods to either prevent or treat this condition. It is well known that with increasing age there is a decrease in skeletal muscle mass and function, with a concurrent infiltration of fat into the muscle (Figure 2).
It has been shown that while older muscle can adapt to anabolic stimuli such as exercise or nutrients the magnitude of the response is reduced. We are currently investigating whether the consumption of fish oil, containing the long chain PUFAs EPA and DHA, can overcome this anabolic resistance and improve the adaptations of older muscle to resistance exercise. In a rat model we have recently shown that fish oil consumption has a tendency to prevent the loss of lean mass with age, with concurrent increases in the anabolic signalling protein p70s6k and increases in whole body glucose turnover (Kamolrat et al., 2012). Furthermore in recent work we have found that after 12 weeks of resistance exercise training, older women consuming fish oil increased their muscle strength and walking speed to a greater extent, almost double, compared to those in the placebo group (Figure 3).
Figure 3: Gait speed in control and fish oils supplemented older women at baseline and after 6 and 12 weeks of resistance exercise training. Data are mean (SD).
In further work we have also recently shown that fish oil supplementation can improve immune function after moderate intensity cycling exercise (Gray et al., 2012) and that high intensity intermittent exercise can be more effective in reducing postprandial lipaemia and oxidative stress after a high fat meal in young healthy men (Gabriel et al., 2012).
Dr. Arimantas Lionikas is interested in identifying the genes and genetic mechanisms controlling the variation seen in muscle mass and strength using an in vivo model. He uses a forward genetics approach to search for such genes, i.e., proceeding from the phenotypic difference to its underlying cause, in a mouse model. There are large differences in muscle size among various inbred strains. He uses genome wide association analyses to identify and then refine the genomic regions (quantitative trait loci; QTL) contributing to these differences. A typical QTL spans over at least several Mb of the genome which harbour many genes. To identify among those the causative gene(s) genomic and transcriptomic analyses are performed in a search for the polymorphic and/or differentially expressed candidates. These candidate genes are then examined in cell culture and knockout models to validate their effects on skeletal muscle.
The research of Dr. Aivaras Ratkevicius’s group centres on metabolic control and obesity. They have recently identified a genetic polymorphism, H55N substitution that could be causing a decrease in enzyme activity of citrate synthase in A/J mice. This might have important implications for metabolic control and the preponderance to obesity of this mouse strain. It is likely that metabolic effects of the H55N polymorphism could be associated with reduced activity of mitochondrial citrate synthase (CS) and altered mitochondrial function. However, the exact mechanism is unclear. They are currently studying metabolic consequences of H55N substitution and suppression of Cs gene expression in different experimental models including E. coli, C2C12 muscle cells and congenic mice. PhD student Mrs Yosra Alhindi, in a collaboration with Dr. Arimantas Lionikas, Dr. Lobke Vaanholt and Professor John Speakman from the School of Biological Sciences (University of Aberdeen) is investigating the effects of the H55N polymorphism on the whole body metabolism in mice. Dr. Stuart Gray and PhD student Mr. Brendan Gabriel are involved in a collaborative project aimed at understanding metabolic effects of low citrate synthase activity in muscle cells.
- Gabriel B, Ratkevicius A, Gray P, Frenneaux M, & Gray SR (2012). High intensity exercise attenuates postprandial lipaemia and markers of oxidative stress. Clin Sci (Lond) 123, 313-321
- Gray P, Gabriel B, Thies F, & Gray SR (2012). Fish oil supplementation augments post-exercise immune function in young males. Brain, Behavior, and Immunity 26 (8) Nov 2012 1265–1272
- Kamolrat T, Gray SR, & Carole TM (2012). Fish oil positively regulates anabolic signalling alongside an increase in whole-body gluconeogenesis in ageing skeletal muscle. Eur J Nutr
- Watt KI, Judson R, Medlow P, Reid K, Kurth TB, Burniston JG, Ratkevicius A, De Bari C, & Wackerhage H (2010). Yap is a novel regulator of C2C12 myogenesis. Biochem Biophys Res Commun 393, 619-624