Author:
Hiam Danielle,Landen Shanie,Jacques Macsue,Voisin Sarah,Lamon Séverine,Eynon Nir
Abstract
Abstract
Background
Sex differences in microRNA (miRNA) expression profiles have been found across multiple tissues. Skeletal muscle is one of the most sex-biased tissues of the body. MiRNAs are necessary for development and have regulatory roles in determining skeletal muscle phenotype and have important roles in the response to exercise in muscle. Yet there is limited research into the role and regulation of miRNAs in the skeletal muscle at baseline and in response to exercise, a well-known modulator of miRNA expression. The aim of this study was to investigate the effect of sex on miRNA expression in the skeletal muscle at baseline and after an acute bout of high-intensity interval exercise. A total of 758 miRNAs were measured using Taqman®miRNA arrays in the skeletal muscle of 42 healthy participants from the Gene SMART study (23 males and 19 females of comparable fitness levels and aged 18–45 years), of which 308 were detected. MiRNAs that differed by sex at baseline and whose change in expression following high-intensity interval exercise differed between the sexes were identified using mixed linear models adjusted for BMI and Wpeak. We performed in silico analyses to identify the putative gene targets of the exercise-induced, sex-specific miRNAs and overrepresentation analyses to identify enriched biological pathways. We performed functional assays by overexpressing two sex-biased miRNAs in human primary muscle cells derived from male and female donors to understand their downstream effects on the transcriptome.
Results
At baseline, 148 miRNAs were differentially expressed in the skeletal muscle between the sexes. Interaction analysis identified 111 miRNAs whose response to an acute bout of high-intensity interval exercise differed between the sexes. Sex-biased miRNA gene targets were enriched for muscle-related processes including proliferation and differentiation of muscle cells and numerous metabolic pathways, suggesting that miRNAs participate in programming sex differences in skeletal muscle function. Overexpression of sex-biased miRNA-30a and miRNA-30c resulted in profound changes in gene expression profiles that were specific to the sex of the cell donor in human primary skeletal muscle cells.
Conclusions
We uncovered sex differences in the expression levels of muscle miRNAs at baseline and in response to acute high-intensity interval exercise. These miRNAs target regulatory pathways essential to skeletal muscle development and metabolism. Our findings highlight that miRNAs play an important role in programming sex differences in the skeletal muscle phenotype.
Funder
Australian Research Council
National Health and Medical Research Council
Publisher
Springer Science and Business Media LLC
Subject
Cell Biology,Developmental Biology,Plant Science,General Agricultural and Biological Sciences,General Biochemistry, Genetics and Molecular Biology,Physiology,Ecology, Evolution, Behavior and Systematics,Structural Biology,Biotechnology
Reference83 articles.
1. Khramtsova EA, Davis LK, Stranger BE. The role of sex in the genomics of human complex traits. Nat Rev Genet. 2019;20(3):173–90.
2. Oliva M, Munoz-Aguirre M, Kim-Hellmuth S, Wucher V, Gewirtz ADH, Cotter DJ, et al. The impact of sex on gene expression across human tissues. Science. 2020;369(6509):eaba3066.
3. Cui C, Yang W, Shi J, Zhou Y, Yang J, Cui Q, et al. Identification and analysis of human sex-biased MicroRNAs. Genomics Proteomics Bioinformatics. 2018;16(3):200–11.
4. Florijn BW, Bijkerk R, van der Veer EP, van Zonneveld AJ. Gender and cardiovascular disease: are sex-biased microRNA networks a driving force behind heart failure with preserved ejection fraction in women? Cardiovasc Res. 2017;114(2):210–25.
5. Guo H, Ingolia NT, Weissman JS, Bartel DP. Mammalian microRNAs predominantly act to decrease target mRNA levels. Nature. 2010;466(7308):835–40.