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

我的研究计划的长期目标是描述各种损伤后的反应，使人类骨骼肌修复和/或适应运动。我们进行的绝大多数研究都是以年轻健康男性为受试者。潜在的假设是，在男性中观察到的驱动肌肉修复和适应的生物过程在女性中是相似的。最近，我们将男性和女性作为参与者纳入我们所有的研究，以便更具包容性。在我们过去15年的大多数研究中，我们的主要结局指标之一是运动性肌肉损伤（EIMD）后骨骼肌干细胞的反应。我们已经表明，肌肉干细胞反应是相当可预测的，EIMD后24小时干细胞群显著扩增，在EIMD后72小时左右达到峰值，并在EIMD后120小时左右恢复到基线值。我们的实验室为推进EIMD后人类肌肉干细胞功能的理解做出了重大贡献。令我们惊讶的是，当我们在分析中包括男性和女性时，这种可预测的肌肉干细胞反应不再明显。事实上，在男性中观察到的显著的干细胞扩增在进行了一轮破坏性运动的女性中完全不存在。这一发现引出了一个重要的问题，即驱动男性和女性骨骼肌修复和适应的过程是否完全相同。这些观察结果也使我们质疑女性肌肉收缩的损伤反应是否比男性减弱。女性EIMD后肌肉干细胞反应减弱（或完全缺失）是否可能限制适应和重塑能力？此外，什么是基于性别的上游因素（细胞因子反应和其他解剖因素，如毛细血管密度和毛细血管与肌肉干细胞的接近度）的差异，调节肌肉干细胞对运动的反应。或者，可能是女性在运动后对肌肉损伤不太敏感，肌肉干细胞反应对于驱动适应是不必要的。本提案的短期目标旨在通过以下方式解决这些问题：1.我们将彻底描述男性和女性急性运动后骨骼肌损伤的特征。2.我们将质疑雌激素对女性肌肉损伤具有保护作用的观点。3.我们将在男性和女性中使用彻底的时间过程研究设计来表征肌肉干细胞对损伤的反应。4.我们将研究急性细胞因子和生长激素的反应后，在男性和女性的损害，并评估重要的解剖关系，已知影响肌肉干细胞功能。

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.