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Publication
Sex differences in skeletal muscle revealed through fiber type, capillarity, and
transcriptomics profiling in mice.
Authors O'Reilly J, Ono-Moore KD, Chintapalli SV, Rutkowsky JM, Tolentino T, Lloyd KCK,
Olfert IM, Adams SH
Submitted By Submitted Externally on 1/10/2022
Status Published
Journal Physiological reports
Year 2021
Date Published 9/1/2021
Volume : Pages 9 : e15031
PubMed Reference 34545692
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, 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.




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