Abstract
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 2 = 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.
Highlights
The molecular underpinnings of sex-specific functional and metabolic characteristics in skeletal muscle remain to be fully elaborated
Animal models have the advantage of precise control over diet, environment, age, and genetics, which enables a comprehensive assessment of innate sex differences in muscle fiber type, capillarity, and molecular phenotypes, including the transcriptome
These results demonstrate that capillary density (# of capillaries/mm2) and capillary:fiber ratio were lower in the GA muscle was sub-divided into superficial (GA-s) muscle in females, and the C:F was lower in extensor digitorum longus (EDL) when compared to males
Summary
The molecular underpinnings of sex-specific functional and metabolic characteristics in skeletal muscle remain to be fully elaborated. Sexual dimorphism in performance and fatigue may be driven by differences in myofiber characteristics, muscle size or other factors such as blood supply (capillarity) Strength indices such as single “rep” maximum force (1RM, in Newtons) for leg or arm resistance exercise are tightly correlated to the whole muscle cross-sectional area (CSA), typically higher in males (Miller et al, 1993). Animal models have the advantage of precise control over diet, environment, age, and genetics, which enables a comprehensive assessment of innate sex differences in muscle fiber type, capillarity, and molecular phenotypes, including the transcriptome As for the latter, there have been surprisingly few published reports in this regard, i.e., transcript profiling of murine mixed muscle by Yang et al (2006) and Yoshioka et al (2007), respectively, with the latter group only comparing one pooled sample per sex. This prompted the current set of experiments to determine and compare myofiber, capillarity, and transcriptomics variables across mixed muscle (gastrocnemius) and myoglobin-rich soleus muscle in male and female mice
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