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

我的研究计划的长期目标是表征各种损伤后反应，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用年轻健康男性作为研究对象进行的。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对女性来说是相似的。最近，为了更具包容性，我们在所有的研究中都纳入了男性和女性参与者。在过去15年的大多数研究中，我们的主要结果测量之一是运动诱导肌肉损伤（EIMD）后骨骼肌干细胞的反应。我们已经表明，肌肉干细胞的反应是相当可预测的，在EIMD后24小时，干细胞数量显著增加，在72小时左右达到峰值，在EIMD后120小时左右恢复到基线值。我们的实验室在促进对EIMD后人类肌肉干细胞功能的理解方面做出了重大贡献。令我们惊讶的是，当我们将男性和女性纳入我们的分析中时，这种可预测的肌肉干细胞反应不再明显。事实上，在进行了一次破坏性的运动后，在男性身上观察到的显著的干细胞扩张在进行了相同的相对运动的女性身上完全没有。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对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）是否可能限制了适应和重塑的能力？此外，调节肌肉干细胞对运动的反应的上游因素（细胞因子反应和其他解剖学因素，如毛细血管密度和毛细血管与肌肉干细胞的接近程度）的性别差异是什么？另一种可能是，女性在运动后不太容易受到肌肉损伤，肌肉干细胞反应不是驱动适应的必要条件。本建议的短期目标旨在以下列方式解决这些问题：我们将彻底表征骨骼肌损伤后急性发作的运动在男性和女性。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. 我们将研究男性和女性损伤后的急性细胞因子和生长激素反应，并评估已知影响肌肉干细胞功能的重要解剖关系。

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.