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The objective of this study was to examine the influence of age on food intake, tissue and organ mass and NF-ĸB and SIRT6 levels in various tissues. The transcription factor, Nuclear Factor Kappa-B (NF-ĸB), is associated with both catabolic and anabolic pathways of muscle metabolism and may be involved in age-related muscle loss. SIRT6 is a member of the sirtuin family of proteins that function as protein lysine deacetylases and are associated with longevity in a number of organisms. Male Sprague-Dawley rats, aged 6 months (Adult) and 21 months (Old) were fed a commercially available diet for 10-17 days. Old rats consumed less food per body weight (BW) each day than Adult rats (1.45% g diet/g BW vs. 2.4% g diet/g BW). However, when intake data were expressed as g/diet per day there was no significant difference between groups. For skeletal muscle tissue, the average mass of gastrocnemius and soleus (g muscle/g BW) was significantly lower in Old rats. Levels of NF-ĸB (p65/RelA) and SIRT6 were measured by Western blot analysis in gastrocnemius, tibialis anterior, quadriceps, soleus, lung, heart, kidney and liver. NF-ĸB levels were higher in gastrocnemius of Old rats compared to Adult rats. No significant age-specific differences in SIRT6 protein levels were noted in the tissues examined. Interestingly, when examined independent of age, levels of SIRT6 were significantly different between certain tissues. Data from this study suggest that age affects muscle loss and NF-ĸB in a tissue-specific manner. Furthermore, these findings indicate tissue-specific but not age-specific differences in SIRT6 protein levels.

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Muscle disorders and induced muscle atrophy impose critical risks to the well-being of an individual, limiting normal activities of daily living. Several resistance training methods have effectively reversed the progression of muscle atrophy. Weightlifting and hydrotherapy are the two widely practiced schemes for resistance training; however, there is the potential risk of excessive loads exerted on the muscles during weightlifting, and limited accessibility and cost are barriers to hydrotherapy. An alternative is using a resistance band. Some limitations include engaging multiple muscles/joints while only unidirectional resistance is feasible. To address these limitations, a VAriable Resistance Suit (VARS) was designed to provide speed-dependent, bi-directional, and variable resistance at a single joint. As a proof of concept, an elbow module of VARS was developed and validated experimentally through a pilot study [15]. This thesis aims to investigate the feasibility of modulating speed-dependent and adjustable resistance at the targeted joints using a VAriable Resistance Suit and investigate the efficacy of the Variable Resistance Suit to induce muscle hypertrophy. The pilot study shows the changes in flexor and extensor muscle activations in response to eight different levels of resistance modulated by VARS. Furthermore, the evaluation of training using VARS on muscle hypertrophy with a focus on the increase in muscle size and strength has been conducted through a prolonged study involving 12 participants. Some sections of this thesis are reused from our published conference paper which I co-author [15].

Skeletal muscle is a plastic tissue capable of responding to environmental perturbations. Increased loading via resistance exercise (RE) activates muscle protein synthesis (MPS) and, to a lesser extent, muscle protein breakdown (MPB). The ingestion of protein further stimulates MPS and suppresses MPB, inducing a positive net protein balance and protein accretion – i.e., muscle hypertrophy. In contrast, muscle unloading reduces MPS, which is thought to be the key driver underpinning skeletal muscle atrophy. The degree of muscle hypertrophy and atrophy in response to loading and unloading varies significantly between individuals and provides an opportunity to investigate the molecular regulators of skeletal muscle remodelling. To that end, we developed a novel unilateral model in which one leg was subjected to RE to induce hypertrophy (Hyp) and the contralateral limb was immobilized to induce atrophy (At). In study 1, we characterized the morphological changes induced by our HypAt model and validated the use of ultrasonography to measure changes in muscle size in both limbs. We discovered that by assessing the differential change in muscle size between legs we reduced the coefficient of variation between subjects. This enabled a more in-depth means-based characterization of the molecular regulators of skeletal muscle remodelling. Indeed, we discovered significantly more genes regulated by muscle remodelling than similarly-sized studies. We also identified a transcriptional signature that scaled with lean mass gains in three independent cohorts and included RNA species that were only modulated at their untranslated regions. Finally, in study 3 we simultaneously measured MPS and MPB in response to short-term immobilization (4 days) and demonstrated for the first time that MPB is statistically unchanged by unloading. Taken together, these studies contribute significantly to our understanding of skeletal muscle remodelling under different loading states and provide a valuable hypothesis-generating resource for future research in the field. / Thesis / Doctor of Philosophy (PhD) / Adaptations of skeletal muscle to loading and unloading are variable between individuals. Herein, we employed a unilateral approach to better understand the drivers of this variability by assessing the influence of resistance training (RT) and disuse on muscle protein turnover and gene expression. First, we validated the use of ultrasound for measuring changes in muscle size in response to loading and unloading. We then identified thousands of genes regulated by loading status and discovered many that were correlated with lean mass gain – some of which would not have been detected without our model. We also demonstrated that RT-induced increases in muscle protein synthesis were not associated with changes in muscle size; however, reductions in muscle protein synthesis were associated with the degree of muscle atrophy observed in response to disuse. Together, these studies contribute significantly to our understanding of how skeletal muscle size is regulated by muscle loading and unloading.

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