Gender gaps, so often the stuff of controversy, are more apt to inspire calm deliberation when they occur in the genome. There, they may be taken as opportunities to better understand our biology, and to develop diagnostic and therapeutic approaches that account for gender differences. Such differences, at the molecular level, may simply indicate that men and women have different baselines, for example, with respect to gene expression.

If reference baselines can be established, they can clarify what constitutes health or illness. Progress toward one such reference baseline has been reported by scientists based at the Karolinska Institute. These scientists, led by Carl Johan Sundberg, Ph.D., a professor of molecular and applied exercise physiology, chose to examine samples of human skeletal muscle and generate complete transcriptomes, the better to “see” which genes are active in skeletal muscle at a given time.

The researchers' results appeared in the October issue of the FASEB Journal, in an article entitled, “The human skeletal muscle transcriptome: sex differences, alternative splicing, and tissue homogeneity assessed with RNA sequencing.”

“We provide extensive information on the skeletal muscle transcriptome, including five previously unannotated protein-coding transcripts,” wrote the authors. “Global transcriptional tissue homogeneity was strikingly high, within both a specific muscle and the contralateral leg.”

Of particular interest were the sex differences that were uncovered. For example, among the 23,000+ known isoforms identified by the researchers, more than 5,000 were found to differ between the sexes.

“The female and male transcriptome was enriched for genes associated with oxidative metabolism and protein catabolic processes, respectively,” the authors of the FASEB Journal article continued. “The data demonstrate remarkably high tissue homogeneity and provide a deep and extensive baseline reference for the human skeletal muscle transcriptome, with regard to alternative splicing, novel transcripts, and sex differences in functional ontology.”

Besides finding never-before-detected gene activity, the researchers determined that men have approximately 400 more active genes in their skeletal muscle than women have.

To arrive at their results, the researchers analyzed RNA sequencing data from a large set of human muscle biopsies. Dr. Sundberg and colleagues recruited nine male and nine female volunteers. Under local anesthesia, researchers extracted small pieces of skeletal muscle from both legs of each study participant. Gene transcripts were isolated from the muscle pieces and then sequenced, so that the code for all transcripts could be used for comparing samples within a muscle, between individual legs and between men and women. Results from this study produced the whole transcriptome of human skeletal muscle in both men and women.

“I hope that the gene activity results from this study will become a reference for human skeletal muscle and provide the basis for many new studies investigating skeletal muscle in different diseases and dysfunctions,” said Maléne Lindholm, a researcher in Prof. Sundberg's research team at Karolinska's Department of Physiology and Pharmacology. “In that way, we can understand our muscles better and possibly develop more optimal treatments and a more personalized healthcare.”

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