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，这些反应允许人类骨骼肌修复和/或适应运动。我们进行的绝大多数研究都是以年轻健康的男性为对象进行的。基本的假设是，在男性身上观察到的推动肌肉修复和适应的生物过程与女性相似。最近，我们在所有研究中都纳入了男性和女性作为参与者，以便更具包容性。在过去15年的大多数研究中，我们的主要结果指标之一是运动性肌肉损伤(EIMD)后骨骼肌干细胞的反应。我们已经证明，肌肉干细胞的反应是非常可预测的，在EIMD后24小时，干细胞数量显著增加，在EIMD后72小时左右达到峰值，并在EIMD后大约120小时恢复到基线水平。我们的实验室在促进对EIMD后人类肌肉干细胞功能的了解方面做出了重大贡献。令我们惊讶的是，当我们在分析中同时包括男性和女性时，这种可预测的肌肉干细胞反应不再明显。事实上，男性在一轮破坏性运动后观察到的显著干细胞扩张，在进行了相同相对运动的女性中完全没有。这一发现回避了一个重要的问题，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。这些观察也让我们质疑，与男性相比，女性对肌肉收缩的损害反应是否减弱。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，如毛细血管密度和微血管与肌肉干细胞的接近程度)在性别上有何差异。另一种可能是，女性在运动后不太容易受到肌肉损伤的影响，肌肉干细胞反应不是驱动适应所必需的。这项提案的短期目标旨在通过以下方式解决这些问题：1.我们将彻底描述急性运动后男性和女性骨骼肌损伤的特征。2.我们将询问雌激素对女性肌肉损伤具有保护作用的概念。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，并评估已知的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.