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Physical inactivity, advancing age, limb immobilization, degenerative diseases and various systemic diseases (many cancers, sepsis, HIV, COPD, kidney disease) all lead to skeletal muscle wasting. The loss of muscle mass is of major clinical importance because it leads to an increased risk for morbidity, disability, and the loss of independence; collectively contributing to a substantive increase in healthcare utilization and cost. The prevalence of cachexia (disease-induced muscle wasting) can reach as high as 80% in certain patient populations and the average cost per hospital stay is $4,641 more than in non-cachectic patients. Direct healthcare costs attributable to sarcopenia were estimated to be $18.5 billion in 2002. Therefore, developing effective skeletal muscle restoration therapies is critical to improve quality of life and prolong functional independence in the broad patient population afflicted by the loss of muscle mass. There are few promising strategies emerging to treat loss of muscle mass. Currently, exercise (e.g., resistance training) is the most effective lifestyle intervention used to promote muscle growth, and testosterone is a well-known pharmacological intervention used to increase muscle mass. A greater understanding of the underlying cellular mechanisms that promote muscle growth and adaptation in response to exercise and pharmacological agents will enable the design of more targeted and effective interventions. Moreover, identifying the mechanisms that regulate muscle growth provides an opportunity to discover novel therapeutic targets for those who cannot or are unwilling to participate in exercise. In particular, a fundamental understanding of the role of muscle stem cells (satellite cells) during regeneration and recovery from volumetric muscle loss made targeting and improving satellite cell function and restorative capacity during these conditions possible. Gaining an in depth understanding for the function of satellite cells during muscle growth may likewise allow them to be targeted and increase their ability to promote muscle growth. Our lab previously showed that while a lack of satellite cells does not limit short-term muscle growth, satellite cells are required to support sustained growth, at least in the plantaris (100% type 2 fibers). As myonuclear accretion and satellite cell abundance are tightly associated with growth in satellite cell replete muscle, the compensatory pathways activated in the absence of satellite cell fusion to enable short-term muscle growth are of interest. In line with this, the mechanism precipitating a shift in the requirement for satellite cells during sustained muscle growth remains to be elucidated. Due to the method of mechanical overload (synergist ablation) used to induce muscle growth in previous studies, our understanding for satellite cell-mediated muscle growth in adult mice is currently restricted to the plantaris. Emerging evidence suggests that these findings may not extend to muscles with a more oxidative phenotype, like the soleus (50% type 1 and 50% type 2) or to muscles which are undergoing robust metabolic adaptations in response to exercise. Whether these finding extend to testosterone induced muscle growth is currently unknown. The mode and length of perturbation utilized to induce muscle growth, the duration of satellite cell depletion, the timing of depletion (pre, post or at some point during adaptation) all may influence requirements for satellite cells. In order to address these gaps in our understanding of the regulation of muscle growth, I utilized the Pax7-DTA mouse strain, which allows for the inducible depletion of satellite cells and 3 distinct interventions to drive muscle growth and adaptation. I utilized testosterone to determine if testosterone-induced myonuclear accretion by satellite cells is required for skeletal muscle hypertrophy (Chapter 2), a lifelong wheel running stimulus to determine if reduced satellite cell content throughout adulthood influences the transcriptome-wide response to physical activity and diminishes the adaptive response of skeletal muscle Chapter (3) and a short (4-wk) and long (8-wk) term weighted wheel running model to induce hypertrophy in the plantaris and soleus to determine the muscle-specific requirements for satellite cells during growth and elucidate the intracellular mechanisms regulating satellite cell independent and dependent muscle growth over a time course of muscle hypertrophy (Chapter 4). My overarching hypothesis is that satellite cells are required for growth in response to exercise induced muscle growth and that these requirements are more stringent in muscles with an oxidative phenotype. The findings from these studies will enhance the ability to target satellite cells as a method to increase muscle mass and provide information necessary to evaluate the therapeutic potential of this strategy, and potentially identify compensatory mechanisms enabling growth in the absence of satellite cells that may also be potential therapeutic targets. The findings from these studies show that while satellite cells are not required for skeletal muscle hypertrophy, they are critical for optimal adaptation to exercise, including maximal muscle growth. Our results show distinct differences for the reliance on satellite cells based on the stimulus used to induce muscle growth and length of the intervention. We show no differences in SC+ and SC- muscle growth in response to testosterone, but blunted growth and adaptation in response to short and long term exercise. This may be due to an inability of resident myonuclei to meet the increased transcriptional demands of metabolic adaptation to exercise in the absence of satellite cell communication and myonuclear addition. In response to lifelong wheel running we show myonuclear fusion in the soleus and increased GPCR signaling in the plantaris which are absent in SC- skeletal muscle and likely contributed to blunted adaptation. In response to 4-weeks and 8-weeks of weighted wheel running, our transcriptional data reveal an aberrant response in SC- skeletal muscle leading to a maladaptive response in the soleus, including a failure to promote ECM remodeling, attenuated capillarization and muscle growth. To what extent these processes are related directly to fusion or more related to satellite cell related signaling to the muscle fiber and other cell types remains to be established., © 2020 Davis A. Englund