Mechanisms underlying sex-based differences in skeletal muscle repair and adaptation

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The long-term goal of my research program is to characterize the various post-damage responses that allow human skeletal muscle to repair and/or adapt to exercise. The vast majority of the studies we have conducted were carried out using young healthy males as subjects. The underlying assumption being that the biological processes driving muscle repair and adaptation observed in males would be similar for females. Recently, we have included both males and females as participants in all of our studies in order to be more inclusive. One of our primary outcome measures, in most of our studies over the last 15 years, is the skeletal muscle stem cell response following exercise-induced muscle damage (EIMD). We have shown that the muscle stem cell response is quite predictable, with a significant expansion of the stem cell population 24h following EIMD, peaking around 72h and returning to baseline values by around 120h post EIMD. Our lab has made significant contributions to advancing the understanding of muscle stem cell function in humans following EIMD. Much to our surprise, this predictable muscle stem cell response was no longer apparent when we included both males and females in our analysis. In fact, the significant stem cell expansion observed in males following a damaging bout of exercise was entirely absent in females who had performed the same relative bout of exercise. This finding begs the important question of whether the processes that drive skeletal muscle repair and adaptation in males and females are the same, at all. These observations also lead us to question whether the damage response to muscle contraction in females is attenuated compared to males. Is it possible that an attenuated (or completely absent) muscle stem cell response following EIMD in females limits capacity for adaptation and remodeling? Additionally, what are the sex-based differences in the upstream factors (cytokine responses and other anatomical factors such as capillary density and proximity of capillaries to muscle stem cells) that regulate the muscle stem cell response to exercise. Alternatively, it may be that females are less susceptible to muscle damage following exercise and a muscle stem cell response is not necessary to drive adaptation. The short-term objectives of this proposal aim to address these issues in the following way: 1. We will thoroughly characterize skeletal muscle damage following an acute bout of exercise in both males and females. 2. We will interrogate the notion that estrogen confers a protective benefit against muscle damage in females. 3. We will characterize the muscle stem cell response to damage using a thorough time-course study design in both males and females. 4. We will investigate the acute cytokine and growth hormone responses following damage in both males and females and assess important anatomical relationships known to impact muscle stem cell function.