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The androgen hormone is responsible for the growth of secondary sex characteristics in humans, such as skeletal muscle. Upon an exercise stimulus, the androgen receptor (AR) plays a crucial role in transmitting the androgenic signal to the nucleus which upregulates transcription of target genes related to growth of skeletal muscle. AR content has been implicated in the hypertrophic response between high and low responders following resistance exercise training (RET) in males. Little is known of the impact of AR expression on acute skeletal muscle damage and whether AR may influence the adaptive response to RET in females. This study aimed to investigate acute changes to AR content following a single bout of muscle damage-inducing exercise as well as sex differences during skeletal muscle repair and hypertrophy. A skeletal muscle biopsy from the vastus lateralis was obtained from 26 healthy, young males (n=13) and females (n=13) at baseline and 48 hours following a single bout of 300 eccentric contractions of the quadriceps. Subsequently, participants performed whole-body RET 4 times a week for 10 weeks, followed by a final skeletal muscle biopsy under resting conditions. Females had greater AR mRNA than males at baseline (~53%) and post-damage (~126%; p<0.05) while AR protein content increased in both sexes similarly following a single bout of eccentric exercise (p<0.05). Damage- and RET-induced satellite cell response was associated with percent change in AR protein content in a sex-specific manner (p<0.05). RET-induced percent change in nuclear AR content was ~17% greater in males compared to females (p<0.05). Interestingly, following RET, males experiencing the highest percent change in myofibre cross sectional area (CSA) exhibited greater changes in nuclear-associated AR protein content compared to females with the highest percent change in CSA. Collectively, AR protein content is elevated following acute eccentric exercise and 10 weeks of RET. Findings from this study suggests that males are more reliant on AR-related mechanisms than females to induce skeletal muscle hypertrophy following RET. / Thesis / Master of Science in Kinesiology / Skeletal muscle is crucial for proper function and activities of daily living. Many factors can regulate the amount and quality of skeletal muscle such as the expression of a protein known as the androgen receptor (AR). The AR plays a role in many cellular pathways that can ultimately dictate the growth and size of a particular tissue like skeletal muscle. There is currently minimal research about AR during skeletal muscle damage and in female skeletal muscle. Understanding how exercise increases AR content in males and females could progress our knowledge of how muscle adapts differently to exercise between sexes. Therefore, the purpose of this study was to understand how the AR behaves in the muscle, in males and females, after a single session of exercise that damages the muscle or after long term resistance exercise (RE). We observed that the AR gene is more abundant in females than males at rest and following damaging exercise. Furthermore, we show that AR protein content increases in both sexes following a single session of damaging exercise and after chronic RE. Muscle stem cells are a component of the muscle that helps to heal muscle after exercise has been performed. In the current study, we demonstrate that AR has a closer relationship to muscle stem cells in males relative to females. Further, AR seems to be more closely linked to muscle growth in males than females. Altogether, AR is a component of the muscle that adapts to exercise differently in males and females. This study may, in part, explain how skeletal muscle responds differently between sexes after exercise.

<p>Adult skeletal muscle has the remarkable capacity of regenerating in response to stressors, such as overuse, injury, or myopathic conditions. A fundamental contributor to the regenerative process is satellite cells, which are the primary stem cells of skeletal muscle. Uncovering factors involved in satellite cell function will greatly improve their therapeutic potential, especially for patients suffering from myopathic diseases.</p> <p>The protein Xin was previously identified as being highly upregulated in damaged skeletal muscle and localized to the satellite cell population, however its purpose there has not been elucidated. Therefore the overall goal of this study was to determine the role of Xin during skeletal muscle regeneration and within its resident stem cell population. This was approached using Xin knockdown (Xin shRNA) and knockout (Xin-/- mice) models, whereby any deficits or changes in the regenerative process can be attributed to the lack/absence of Xin. The results of the following studies reveal that when Xin expression is reduced or absent, muscle regeneration is impaired, satellite cell activation is altered, and muscle fiber morphology moves towards a myopathic state.</p> <p>Furthermore, since Xin has been shown to be upregulated during regeneration, it was interesting to study the expression of Xin in human myopathic muscle which is in a constant state of regeneration. It was observed that Xin expression correlates with degree of damage in myopathic muscle, regardless of disease diagnosis. Therefore, these data have improved our understanding of muscle regeneration, satellite cell function, and suggest a clinical marker for defining muscle damage severity.</p> / Master of Science (MSc)

There is growing appreciation of the potential for high intensity interval training (HIT) to rapidly stimulate metabolic adaptations that resemble traditional endurance training, despite a low total exercise volume. However, much of the work has been conducted on young active individuals and the results may not be applicable to older, less active populations. In addition, many studies have employed "all out", variable-load exercise interventions (e.g., repeated Wingate Tests) that may not be safe, practical or well tolerated by certain individuals. We determined the effect of a short program of low-volume, submaximal, constant-load HIT on skeletal muscle oxidative capacity and insulin sensitivity in sedentary middle-aged individuals who may be at higher risk for inactivity-related chronic diseases. Sedentary but otherwise healthy men (n=3) and women (n=4) with a mean (±SE) age, body mass index and peak oxygen uptake (VO_2peak) of 45±2 yr, 27±2 kg-m^2 and 30±1 ml·kg^-1·min^-1 were recruited. Subjects performed 6 training sessions over 2 wk, each consisting of 10 x 1 min cycling at 60% of peak power elicited during a ramp VO_2peak test (<90% of heart rate reserve) with 1 min recovery between intervals. Needle biopsy samples (v. lateralis) were obtained before training and <72 h after the final training session. Muscle oxidative capacity, as reflected by the maximal activity and protein content of citrate synthase, increased by ~20% after training, which is similar to changes previously reported after 2 wk of Wingate-based HIT in young active subjects. Insulin sensitivity, based on fasting glucose and insulin, improved by ~35% after training. These data support the notion that low-volume HIT may be a practical, time- efficient strategy to induce metabolic adaptations that reduce the risk for inactivity-related disorders in previously sedentary adults. / Thesis / Master of Science (MSc)

Protein arginine methyltransferase 1 (PRMT1), -4 (also known as coactivator-associated arginine methyltransferase 1; CARM1), and -5 catalyze the methylation of arginine residues on target proteins. In turn, these marked proteins mediate a variety of biological functions. By regulating molecules that are critical to the remodelling of skeletal muscle phenotype, PRMTs may influence skeletal muscle plasticity. Our study tests the hypothesis that the intracellular signals required for muscle adaptation to exercise will be associated with the induction of PRMT expression and activity. C57BL/6 mice were assigned to one of three experimental groups: sedentary (SED), acute bout of exercise (0PE), or acute exercise followed by 3 hours of recovery (3PE). The mice in the exercise groups performed a single bout of treadmill running at 15 m/min for 90 minutes. We observed that PRMT gene expression and global enzyme activity are muscle- specific, generally being higher in slow, oxidative muscle, as compared to faster, more glycolytic tissue. Despite the activation of canonical exercise-induced signalling involving AMPK and PGC-1α, PRMT expression and activity at the whole muscle level were unchanged. However, subcellular analysis revealed the exercise-evoked myonuclear translocation of PRMT1 prior to the nuclear translocation of PGC-1α, which colocalizes the proteins within the organelle after exercise. Acute physical activity also augmented the targeted methyltransferase activities of CARM1, PRMT1, and -5 in the myonuclear compartment, suggesting that PRMT-mediated histone arginine methylation is an integral part of the early signals that drive skeletal muscle plasticity. In summary, our data supports the emergence of PRMTs as important players in the regulation of skeletal muscle plasticity. / Thesis / Master of Science (MSc) / Skeletal muscle is a plastic tissue that can adapt to various physiological demands. Previous work suggests that protein arginine methyltransferases (PRMTs) are important in the regulation of skeletal muscle remodeling. However, their role in exercise-induced skeletal muscle plasticity is unknown. Therefore, the purpose of this study was to investigate the association between the intracellular signals required for muscle adaption and various metrics of PRMT biology. Our data demonstrate that PRMTs exhibit muscle-specific expression and function in mice. The movement of PRMT1 into myonuclei increased following exercise, while the specific methylation status of PRMT targets were also elevated. Overall, our data suggests that muscle-specific PRMT expression may be important for the determination and/or maintenance of different fiber type characteristics. Moreover, distinct PRMT cellular localization and methyltransferase activity may be key signals that contribute to skeletal muscle phenotypic plasticity.

Despite the emerging importance of protein arginine methyltransferases (PRMTs) in regulating skeletal muscle plasticity, the biology of these enzymes during muscle development remains poorly understood. Therefore, our purpose was to investigate PRMT1, -4, and -5 expression and function in skeletal muscle cells during the phenotypic remodeling elicited by myogenesis. C2C12 muscle cell maturation, assessed during the myoblast stage, and during days 1, 3, 5, and 7 of differentiation, was employed as an in vitro model of myogenesis. We observed PRMT-specific patterns of expression and activity during myogenesis. PRMT4 and -5 gene expression was unchanged, while PRMT1 mRNA and protein content were significantly induced. Cellular monomethylarginines and symmetric dimethylarginines, indicative of global and type II PRMT activities, respectively, remained steady during development, while type I PRMT activity indicator asymmetric dimethylarginines increased through myogenesis. Histone 4 arginine 3 (H4R3) and H3R17 contents were elevated coincident with the myonuclear accumulation of PRMT1 and -4. Collectively, this suggests that PRMTs are methyl donors throughout myogenesis and demonstrate specificity for their protein targets. Cells were then treated with TC-E 5003 (TC-E), a selective inhibitor of PRMT1 in order to specifically examine the enzymes role during myogenic differentiation. TC-E treated cells exhibited decrements in muscle differentiation, which were consistent with attenuated mitochondrial biogenesis and respiratory function. In summary, this study increases our understanding of PRMT1, -4, and -5 biology during the plasticity of skeletal muscle development. Our results provide evidence for a role of PRMT1, via a mitochondrially-mediated mechanism, in driving the muscle differentiation program. / Thesis / Master of Science (MSc) / Protein arginine methyltransferases (PRMTs) are responsible for many important functions in skeletal muscle. However, significant knowledge gaps exist with respect to PRMT expression and activity during conditions of muscle remodeling. Therefore, the purpose of this Thesis was to investigate PRMT biology throughout skeletal muscle development. Mouse muscle cells were employed to examine characteristics of PRMT1, -4, and -5 at numerous timepoints during myogenesis. PRMTs exhibited distinct patterns of gene expression and activity during muscle maturation. A PRMT1 inhibitor (TC-E) was utilized to investigate the role of this enzyme during myogenesis. Muscle differentiation was impaired in TC-E-treated cells, which coincided with reduced mitochondrial biogenesis and respiratory function. Altogether, these results suggest a PRMT-specific pattern of expression and activity during myogenesis. Furthermore, PRMT1 plays a crucial role in skeletal muscle differentiation via a mitochondrially-mediated mechanism. Our study provides a more comprehensive view on the role of PRMTs in governing skeletal muscle plasticity.

Recent recommendations are that older adults increase their dietary protein intake to intakes higher than are currently recommended to mitigate sarcopenia-induced muscle loss caused in part by anabolic resistance. Protein supplementation may serve as an effective strategy to meet protein intake goals; however, protein supplements vary in their quality, which may impact muscle protein turnover. Protein quality is determined by the digestibility and content of essential amino acids in a protein source and may play an important role in mitigating the loss of muscle mass and muscle protein synthesis (MPS) during energy restriction (ER), acute reductions in physical activity, which we modeled using enforced step reduction (SR), and during recovery from SR. We aimed to determine whether the quality of a protein supplement – whey protein (higher quality) versus collagen peptides (lower quality) – would impact the reduction in fat-free bone-free mass (FBFM) and MPS (Study 1), and also to compare differences in functional variables: strength loss in men and women, and single fibre function with SR in men (Study 2). In Studies 1 and 2 we compared supplementation with whey protein (WP) and collagen peptides (CP), higher and lower quality proteins respectively, as part of a higher protein diet provided to older adults during one week of ER (-500 kcal/d), two weeks of step reduction (< 750 steps/d) (ER+SR) and one week of recovery (RC). Two weeks of ER+SR significantly reduced FBFM in both the WP and CP groups with greater FBFM recovery with WP. MPS was significantly reduced following ER in both groups and did not decrease further during ER+SR. MPS was increased above ER+SR following 1 week of RC in the WP group only. ER+SR significantly reduced maximum voluntary contraction (MVC) in both men and women; however, following RC men fully recovered their strength and women did not. In Study 3, we aimed to determine the impact of WP and CP supplementation combined with unilateral resistance exercise (RE) to augment the acute and longer term MPS response in healthy older women. Acutely, rates of MPS were elevated following WP+RE and with WP alone while MPS was elevated only in CP+RE. Six days of supplementation increased MPS in WP and WP+RE with no increase in MPS with CP or CP+RE. Collectively, these studies demonstrate that protein quality is an important variable to consider in selecting a protein supplement for older adults and for recovering from inactivity. / Thesis / Doctor of Science (PhD) / At the end of the 5th decade of life, adults will have lost an appreciable amount of muscle mass and strength versus what they had in their 3rd decade of life. This age-related loss of muscle mass and strength is known as sarcopenia. Additionally, as they age, adults will experience brief periods of reduced physical activity due to illness, injury, or recovery from surgery. Such periods are associated with a rapid loss of muscle and strength creating a brief period of ‘accelerated sarcopenia’. Strategies to combat the loss of muscle and strength in these periods include increasing protein intake and even periodic exercise which may help to reduce the negative impact of physical inactivity. In particular, higher quality protein sources (protein derived from animal sources or soy) and weightlifting may better help muscles recover from inactivity. Our main findings were that consuming high quality protein (whey protein) stimulated the process of muscle building that is normally reduced with inactivity. Importantly, when combined with resistance exercise, we were able to increase the rate at which healthy older women built muscle with whey protein in comparison to a lower quality protein source (collagen peptides). These findings provide novel and insightful information for the recommendations of protein supplement types to older adults to increase daily protein intake to preserve muscle mass with age.

An investigation into the complex function of muscle using non-invasive imaging and novel analytical approaches. / The human body is inherently complex as seen through the structural organization of muscle in terms of its contractile subunit organization and scaling, innervation patterns, and vascular organization. However, the functional complexity of muscle such as its state of oxygenation, metabolism or blood-flow has been less well explored. Thus in an effort to improve our understanding of muscle, blood oxygenation level dependent (BOLD) magnetic resonance imaging of the lower leg, at rest and during a variety of weighted plantar-flexion paradigms, at 40% maximal voluntary contraction, was employed. Prior to experimentation, on 11 healthy subjects, an ergometer and electromyogram (EMG), suitable for use within the MRI, were constructed to allow for concurrent exercise and image acquisition. After collecting muscle BOLD data, four novel techniques were using to describe muscle function. The first technique used the fractal dimension, a measure of complexity, conveying the rate of variation of muscle blood flow at rest. This technique was able to determine differences between the muscles of lower leg, which have varying distributions of muscle fibre types based on function. The second exploratory technique was the use of the phase space, which provides insight into state/state-transitions of a system over time. The phase space representation of the BOLD signal provided novel insight into the muscle activation state. It demonstrated that muscle has more than the two blood flow states of reduced levels at rest and increased levels when exercising. The third technique involved using a signal saturation (SAT) region, proximal to the imaging region, to mitigate the arterial in-flow effects to more accurately represent muscle activation. By observing the correlation between the ideal reference and recorded signal, the acquisition with the arterial suppression improved the assessment of what regions in the muscle were active in the range borderline activation, which has the highest uncertainty. The final outlook on muscle behaviour involved using measures of fatigue from the collected EMG data to develop novel metrics of fatigue based on the BOLD signal. Concurrent BOLD and EMG of the anterior compartment of the lower leg during a plantar-flexion block design, demonstrated that the change in blood-flow between rest and contracted states is an excellent indicator of muscle fatigue. The primary outlook of this thesis is to provide a unique data collection and analytic framework to describe muscle behaviour, which was achieved using non-invasive measures with a complex outlook. / Thesis / Master of Applied Science (MASc) / The human body is complex, and an incredible amount of research has been done to better understand it. Specifically, muscle is built and works in a complex way to allow us to move and perform everyday tasks. There are many diseases that affect how a muscle works, which is why there is a need to describe muscle performance when it is healthy and unhealthy. In this research, muscle behaviour is explored by taking pictures of the leg. From these pictures the blood flow in the calf and shin was measured both when staying still and when performing exercise. Four new techniques were created to describe the blood flow in the leg. The first technique measured how complex the muscle activity is, while staying still. If blood-flow changes a lot in a short amount of time, it is complex. This showed that the different components of muscle, either used for stamina or power, receive blood differently. The second technique used a different way of looking at the muscle to show that there are many different rates and amounts of blood-flow in the muscle. It revealed that muscle has more than the two blood flow options of 1) the normal level when resting and 2) the increased level when exercising. The third technique involved using an image filter to get a clean image of the muscle without the blood vessels affecting or misrepresenting the image. It was able to show what muscle regions were involved in exercise more accurately than before. The final technique involved measuring muscle electricity and blood flow at the same time, to find out when the muscle was exhausted. It demonstrated that muscle, when exhausted, showed larger changes in blood flow when going from resting to exercising. Overall, this research described how muscle performs in healthy individuals using new techniques. These techniques can now be used to compare healthy muscle to damaged/diseased muscle to determine how the muscle is recovering or to diagnose muscular disease.

Cancer cachexia is a debilitating, paraneoplastic syndrome commonly associated with late stage malignancy. It is estimated that ~25% of cancer-related deaths are due directly to complications arising from cachexia (Barton, 2001). Cachexia manifests as severe body wasting, primarily due to the loss of skeletal muscle mass. This study tested the hypothesis that muscle atrophy associated with cancer cachexia could be attenuated by using a unilateral, functional overload (FO) model applied concurrently with tumor development. To accomplish this, Morris hepatoma MH-7777 cells were implanted in adult female, Buffalo rats (n = 12) and allowed to incubate for 6 weeks. FO surgeries (n = 12) were performed five days prior to MH-7777 cell implantation. Over the course of six weeks, healthy, age, sex and strain-matched, vehicle-injected rats (n = 12) gained ~5% of body weight compared to tumor-bearing rats that lost ~6% of body weight when adjusted for tumor mass. Tumor-bearing animals experienced significant atrophy to gastrocnemius, tibialis anterior, extensor digitorum longus, plantaris and diaphragm muscles. FO successfully reversed plantaris muscle atrophy in cachectic, tumor-bearing rats (n=5). FO plantaris masses were ~24% larger than contralateral controls. However, this hypertrophic response was not as great as FO plantaris muscles from healthy, sham-operated controls (~44% larger than contralateral controls, n=5). FO plantaris muscles from tumor-bearing rats had ~1.5 fold increase in myonuclei/fiber ratios compared those of sham-operated, tumor-bearing controls (n = 6). Therefore, cancer cachexia did not prevent myonuclear accretion necessary for skeletal muscle hypertrophy. Little data exists on adaptations to myosin heavy chain (MHC) isoforms in cachectic skeletal muscle. Plantaris muscles from tumor-bearing rats displayed decreased percentages of MHC type I compared to plantaris muscles from vehicle-injected controls (7% vs. 3%, respectively). However, FO plantaris muscles from tumor-bearing rats had an increased percentage of MHC type I and decreased percentage of MHC type IIb compared to sham-operated tumor-bearing rats, adaptations commonly seen in trained muscles. Therefore, cancer cachexia did not prevent the capability of skeletal muscle to respond normally to hypertrophic stimuli. This study also attempted to characterize a mechanism responsible for the hypertrophic response, increased myonuclei/fiber ratio and transition toward a slower MHC profile in FO plantaris muscles from tumor-bearing rats. Recently, the Ca2+/calmodulin-dependent protein phosphatase, calcineurin, has been suggested as a critical factor regulating skeletal muscle growth and fiber-type dependent gene expression (Chin, 1998; Wu, 2000; Olson, 2000; Otis, 2001). The protein content of the catalytic subunit (CaNa) and the regulatory subunit (CaNb) of calcineurin were unchanged in plantaris muscles from tumor-bearing animals compared to healthy controls. Furthermore, total and specific (normalized to CaNa protein content) calcineurin phosphatase activity were not altered in any group. Therefore, calcineurin activity did not appear to be associated with the regulation of the morphological and physiological response of hypertrophying plantaris muscles in cachectic, tumor-bearing rats. Overall, this study indicated that atrophied plantaris muscles from tumor-bearing animals have a reduced capacity to hypertrophy potentially due to a decreased myonuclei/fiber ratio. Furthermore, it is unlikely that changes to mass and MHC isoform expression are associated with calcineurin phosphatase activity. / Ph. D.

Skeletal muscle can perceive cellular energy status and substrate availability and demonstrates remarkable plasticity in response to environmental changes. Nonetheless, how skeletal muscle and its resident stem cells (satellite cells; SCs) sense and respond to nutrient flux remains largely undefined. The dynamic post-translational modification O-GlcNAcylation has been shown to serve as a cellular nutrient sensor in a wide range of cells and tissues, yet its role in skeletal muscle and SCs remains unexplored. Here, we ablated skeletal muscle O-GlcNAc transferase (OGT), and thus O-GlcNAcylation, and found the knockout mice exhibited enhanced glucose uptake, insulin sensitivity, and resistance to high-fat diet induced obesity. Additionally, mKO mice had a 3-fold increase in circulating levels of interleukin-15 (IL-15), a potent anti-obesity cytokine, potentially through epigenetic regulation of Il15 by OGT. To further investigate if there was a causal relationship between OGT ablation and the lean phenotype, we generated muscle specific OGT and interleukin-15 receptor alpha (IL-15ra) double knockout mice (mDKO). As a result, mDKO mice had blunted IL-15 secretion and minimal protection against HFD-induced obesity. Together, these data indicate the skeletal muscle OGT-IL15 axis plays an essential role in the maintenance of skeletal muscle and whole-body metabolic homeostasis. As satellite cells (SCs) play an indispensable role in postnatal muscle growth and adult regenerative myogenesis, we investigated the role of O-GlcNAcylation in SC function. To this end, we conditionally ablated OGT in SCs (cKO) and found cKO mice had impaired SC proliferation, in vivo cycling properties, population stability, metabolic regulation, and adult regenerative myogenesis. Together these findings show that SCs require O-GlcNAcylation, presumably to gauge nutritional signals, for proper function and metabolic homeostasis. Another critical yet often neglected player in myogenesis are mitochondria. Traditionally depicted as a power plant in cells, mitochondria are critical for numerous nonconventional, energy-independent cellular process. To investigate the role of both mitochondrial energy production and alternative mitochondrial functions in myogenic regulation, we ablated ATP synthase subunit beta (ATP5b) and ubiquinol-cytochrome c reductase (UQCRFS1) in C2C12 myoblasts to disrupt mitochondrial ATP production and mitochondrial membrane potential, respectively. Ablation of UQCRFS1, but not ATP5b, impaired myoblast proliferation, although lack of either gene compromised myoblast fusion. Interestingly, addition of the potent myogenic stimulator IGF-1 rescued ATP5b fusion but could not override UQCRFS1 knockout effects on proliferation or differentiation. These data demonstrate mitochondrial ATP production is not the "metabolic switch" that governs myogenic progression but rather an alternative mitochondrial function. In summary, skeletal muscle and their resident stem cell population (SCs) both use O-GlcNAcylation, feasibly to sense and respond to nutritional cues, for the maintenance of metabolic homeostasis and normal physiology. A deeper understand of both muscle and SC metabolic regulation may provide therapeutic targets to improve global metabolism and muscle growth. / Doctor of Philosophy / Skeletal muscle is responsible for approximately 20% of basal energy expenditure and 70-90% of insulin-mediated glucose disposal, and as such changes in skeletal muscle metabolism and insulin sensitivity have profound impacts on whole body metabolism. Skeletal muscle is a plastic tissue that can perceive nutrient availability, which permits metabolic adaptations to environmental changes. Deletion of the nutrient sensing pathway O-GlcNAcylation in skeletal muscle (mKO) protected mice from high-fat diet induced obesity and ameliorates whole-body insulin sensitivity. Skeletal muscle can secrete myokines to elicit endocrine effects on other tissues in the body, and as such, we proposed perturbation of this nutrient sensing pathway in skeletal muscle alters myokine secretion to elicit responses in other metabolically active tissues to support its energy requirements. Indeed, circulating levels of interleukin-15, a potent anti-obesity myokine, increased 3-fold in mKO mice. To determine the contribution of IL-15 to the mKO phenotype, we used a genetic approach to blunt IL-15 secretion from skeletal muscle (mDKO), which partially negated the lean mKO phenotype. Our findings show the ability of skeletal muscle to "sense" changes in nutrients through O-GlcNAcylation is necessary for proper muscle and whole-body metabolism. Moreover, this nutrient sensing mechanism is also important for proper muscle stem cell function, also known as satellite cells (SCs). Loss of O-GlcNAcylation in SCs impairs their ability to regenerate muscle after injury, which can be attributed to a reduced capacity to proliferate and an inability to maintain a healthy SC population. Interestingly, SCs lacking O-GlcNAcylation have a greater mitochondrial content. Using a myoblast cell line, we investigated the contribution of mitochondria to myogenesis, the formation of muscle, and found mitochondrial energy production is dispensable in the myogenic process. Our studies show skeletal muscle and SCs rely on highly integrated signaling cascades that sense and respond to intrinsic metabolic changes and extrinsic nutritional cues to function properly.