Division of Exercise Physiology, West Virginia University School of Medicine, Morgantown, West Virginia, USA.
Arkansas Children's Nutrition Center, Little Rock, Arkansas, USA.
Physiol Rep. 2021 Sep;9(18):e15031. doi: 10.14814/phy2.15031.
Skeletal muscle anatomy and physiology are sexually dimorphic but molecular underpinnings and muscle-specificity are not well-established. Variances in metabolic health, fitness level, sedentary behavior, genetics, and age make it difficult to discern inherent sex effects in humans. Therefore, mice under well-controlled conditions were used to determine female and male (n = 19/sex) skeletal muscle fiber type/size and capillarity in superficial and deep gastrocnemius (GA-s, GA-d), soleus (SOL), extensor digitorum longus (EDL), and plantaris (PLT), and transcriptome patterns were also determined (GA, SOL). Summed muscle weight strongly correlated with lean body mass (r = 0.67, p < 0.0001, both sexes). Other phenotypes were muscle-specific: e.g., capillarity (higher density, male GA-s), myofiber size (higher, male EDL), and fiber type (higher, lower type I and type II prevalences, respectively, in female SOL). There were broad differences in transcriptomics, with >6000 (GA) and >4000 (SOL) mRNAs differentially-expressed by sex; only a minority of these were shared across GA and SOL. Pathway analyses revealed differences in ribosome biology, transcription, and RNA processing. Curation of sexually dimorphic muscle transcripts shared in GA and SOL, and literature datasets from mice and humans, identified 11 genes that we propose are canonical to innate sex differences in muscle: Xist, Kdm6a, Grb10, Oas2, Rps4x (higher, females) and Ddx3y, Kdm5d, Irx3, Wwp1, Aldh1a1, Cd24a (higher, males). These genes and those with the highest "sex-biased" expression in our study do not contain estrogen-response elements (exception, Greb1), but a subset are proposed to be regulated through androgen response elements. We hypothesize that innate muscle sexual dimorphism in mice and humans is triggered and then maintained by classic X inactivation (Xist, females) and Y activation (Ddx3y, males), with coincident engagement of X encoded (Kdm6a) and Y encoded (Kdm5d) demethylase epigenetic regulators that are complemented by modulation at some regions of the genome that respond to androgen.
骨骼肌解剖学和生理学具有性别二态性，但分子基础和肌肉特异性尚未得到很好的确立。代谢健康、健身水平、久坐行为、遗传和年龄的差异使得很难在人类中辨别内在的性别影响。因此，在严格控制的条件下，使用小鼠来确定雌性和雄性（n = 19/性别）的腓肠肌（GA-s、GA-d）、比目鱼肌（SOL）、趾长伸肌（EDL）和跖肌（PLT）的骨骼肌纤维类型/大小和毛细血管，并确定转录组模式（GA、SOL）。肌肉总重量与瘦体重呈强烈正相关（r = 0.67，p < 0.0001，两性）。其他表型具有肌肉特异性：例如，毛细血管密度（男性 GA-s 较高）、肌纤维大小（男性 EDL 较高）和纤维类型（女性 SOL 中分别为 I 型和 II 型比例较高）。转录组学有很大的差异，有超过 6000 个（GA）和超过 4000 个（SOL）mRNA 因性别而差异表达；这些mRNA 中只有少数在 GA 和 SOL 中共享。途径分析显示核糖体生物学、转录和 RNA 处理存在差异。对 GA 和 SOL 中共享的性别二态性肌肉转录本以及来自小鼠和人类的文献数据集进行策展，确定了 11 个我们认为是肌肉内在性别差异的典型基因：Xist、Kdm6a、Grb10、Oas2、Rps4x（女性更高）和 Ddx3y、Kdm5d、Irx3、Wwp1、Aldh1a1、Cd24a（男性更高）。这些基因和我们研究中表达最高的“性别偏向”基因不包含雌激素反应元件（例外，Greb1），但一部分被认为是通过雄激素反应元件调节的。我们假设，小鼠和人类的内在肌肉性别二态性是由经典的 X 失活（Xist，女性）和 Y 激活（Ddx3y，男性）触发的，同时伴随着 X 编码（Kdm6a）和 Y 编码（Kdm5d）去甲基化酶表观遗传调节剂的共同作用，这些调节剂在基因组的一些区域得到了补充，这些区域对雄激素有反应。
