Sex differences in skeletal muscle revealed through fiber type, capillarity, and transcriptomics profiling in mice

Authors: O'REILLY, JULIANA - West Virginia University; ONO-MOORE, KIKUMI - Arkansas Children'S Nutrition Research Center (ACNC); CHINTAPALLI, SREE - Arkansas Children'S Nutrition Research Center (ACNC); RUTKOWSKY, JENNIFER - University Of California, Davis; TOLENTINO, TODD - University Of California, Davis; LLOYD, K.C. KENT - University Of California, Davis; OLFERT, MARK - West Virginia University; ADAMS, SEAN - University Of California, Davis

Submitted to: Physiological Reports
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 8/19/2021
Publication Date: 9/21/2021
Citation: Jannifer, O., Ono-Moore, K.D., Chintapalli, S.V., Rutkowsky, J.M., Tolentino, T., Lloyd, K., Olfert, M.I., Adams, S.H. 2021. Sex differences in skeletal muscle revealed through fiber type, capillarity, and transcriptomics profiling in mice. Physiological Reports. https://doi.org/10.14814/phy2.15031.
DOI: https://doi.org/10.14814/phy2.15031

Interpretive Summary: It is recognized that muscle anatomy and function differ between males and females, but the underlying mechanisms are not fully understood. A variety of factors like age, physical activity, sedentary behavior etc., can affect muscle function, making it difficult to identify the basic muscle differences between sexes. In this publication, co-operative scientists in Little Rock, Arkansas, studied muscle anatomy and function in male and female rodents. The investigators collected samples from 19 male mice and 19 female mice to determine skeletal muscle fiber types and sizes, as well as number of capillaries (small blood vessels) in five different muscles in the legs. Clear differences were found between sexes, including higher density of capillaries and larger muscle fiber size in some muscles in males, while females showed higher prevalence of slow muscle fibers. Gene expression differences between sexes were also found, and these were dependent on muscle type. Some genes were found to have higher expressions in females, and some had higher expressions in males. It was found that male sex hormones may influence the regulation of some genes of importance for muscle function. Thus, it was suggested that sex chromosomes may regulate processes of importance for muscle function, while distinct differences in specific muscles may be caused by sex differences in later parts of the regulatory pathways. The authors concluded that many knowledge gaps remain before we can conclude about the inherent muscle differences, and about which components can be regulated by factors like fitness/training, metabolic health status, age, hormonal profiles, etc. The paper published significant new knowledge that may be important for human development and growth, exercise science, and potentially also meat production.

Technical 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 (r2 = 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,