Summary: Sex-specific circuits in muscles signal to other tissues and organs, processing muscle impact differently in males and females.

Source: UC Irvine

A new University of California, Irvine-led study identifies sex-specific circuits of muscle signaling to other tissues and that the organs and processes muscle impacts are markedly different between males and females.

This new discovery provides insight into how muscle functions, such as exercise, promote healthy longevity, metabolism and improve cognition. 

The study, titled, “Genetic variation of putative myokine signaling is dominated by biologic sex and sex hormones,” published in eLife, is the first to evaluate how genetic architecture influences muscle signaling to other tissues, highlighting that sex and estrogens are critical determinants of these processes.

“Muscle is critical for maintaining metabolic state and disruption of muscle function is a hallmark of diseases such as obesity, type 2 diabetes and cardiovascular disease,” said senior author Marcus M. Seldin, PhD, assistant professor of biological chemistry at UCI School of Medicine. 

Muscles secrete proteins called myokines, which play roles in a variety of processes by interacting with other tissues.

Essentially, myokines allow skeletal muscles to communicate with organs such as the kidneys, the liver or the brain, which is essential for the body to keep its metabolic balance. Some of the process myokines are involved include inflammation, cancer, the changes brought about by exercise, and even cognition.

Despite the clear relevance of myokines to so many physiological outcomes, the way these proteins are regulated and their effects are not well understood.

For this study, the research team performed a survey of genetic correlations focused on myokine gene regulation, muscle cell composition, cross-tissue signaling and interactions with genetic sex in humans.

While expression levels of a majority of myokines and cell proportions within skeletal muscle showed little relative differences between males and females, nearly all significant cross-tissue enrichments operated in a sex-specific or hormone-dependent fashion; in particular, with estradiol.

University of California, Irvine-led study identifies sex-specific circuits of muscle signaling to other tissues, and that the organs and processes muscle impacts are markedly different between males and females. Credit: UCI

These sex- and hormone-specific effects were consistent across key metabolic tissues: liver, pancreas, hypothalamus, intestine, heart, visceral and subcutaneous adipose tissue.  This study highlighted a few examples such as that muscle signals more to the pancreas in females, compared to males where liver is dominant.   

“We already know that skeletal muscle plays an integral role in coordinating physiologic homeostasis.  In this study, we sought to understand how muscle interacts with metabolic tissues and illustrate the importance of considering the effects of genetic sex and sexual hormones when studying metabolism,” said Seldin. 

Moving forward, the research team plans to generate cell-based systems to evaluate some of the new hormones uncovered as part of this study and investigate why they signal differently between sexes.

Funding: This work was supported by the National Institutes of Health.

About this neuroscience research news

Author: Anne Warde
Source: UC Irvine
Contact: Anne Warde – UC Irvine
Image: The image is credited to UCI

Original Research: Open access.
“Genetic variation of putative myokine signaling is dominated by biologic sex and sex hormones” by Marcus M. Seldin et al. eLife

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Abstract

Genetic variation of putative myokine signaling is dominated by biologic sex and sex hormones

Skeletal muscle plays an integral role in coordinating physiological homeostasis, where signaling to other tissues via myokines allows for coordination of complex processes.

Here, we aimed to leverage natural genetic correlation structure of gene expression both within and across tissues to understand how muscle interacts with metabolic tissues. Specifically, we performed a survey of genetic correlations focused on myokine gene regulation, muscle cell composition, cross-tissue signaling, and interactions with genetic sex in humans.

While expression levels of a majority of myokines and cell proportions within skeletal muscle showed little relative differences between males and females, nearly all significant cross-tissue enrichments operated in a sex-specific or hormone-dependent fashion; in particular, with estradiol. These sex- and hormone-specific effects were consistent across key metabolic tissues: liver, pancreas, hypothalamus, intestine, heart, visceral, and subcutaneous adipose tissue.

To characterize the role of estradiol receptor signaling on myokine expression, we generated male and female mice which lack estrogen receptor α specifically in skeletal muscle (MERKO) and integrated with human data. These analyses highlighted potential mechanisms of sex-dependent myokine signaling conserved between species, such as myostatin enriched for divergent substrate utilization pathways between sexes.

Several other putative sex-dependent mechanisms of myokine signaling were uncovered, such as muscle-derived tumor necrosis factor alpha (TNFA) enriched for stronger inflammatory signaling in females compared to males and GPX3 as a male-specific link between glycolytic fiber abundance and hepatic inflammation. Collectively, we provide a population genetics framework for inferring muscle signaling to metabolic tissues in humans.

We further highlight sex and estradiol receptor signaling as critical variables when assaying myokine functions and how changes in cell composition are predicted to impact other metabolic organs.



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