Genetic variation of putative myokine signaling is dominated by biological sex and sex hormones
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Evaluation Summary:
This elegantly performed systems-genetics paper on the predicted human skeletal muscle secretome highlights the importance of sex and sex hormones in regulating myokine expression and predicted cross-tissue effects. Male and female mice lacking estrogen receptor α (Esr1) were used to understand how estrogen signalling affects myokine genes expression. The methods used and data presented in this manuscript can serve as an important resource for other researchers in the field.
(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #3 agreed to share their name with the authors.)
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Abstract
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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Evaluation Summary:
This elegantly performed systems-genetics paper on the predicted human skeletal muscle secretome highlights the importance of sex and sex hormones in regulating myokine expression and predicted cross-tissue effects. Male and female mice lacking estrogen receptor α (Esr1) were used to understand how estrogen signalling affects myokine genes expression. The methods used and data presented in this manuscript can serve as an important resource for other researchers in the field.
(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #3 agreed to share their name with the authors.)
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Reviewer #1 (Public Review):
This paper is of interest in introducing a human population approach to an examination of differences between male and female expression of human myokines using population genetics approaches. A finding that estradiol signaling modulates myokine expression in both sexes, more so in males, was then explored using similar analyses in genetic murine platforms.
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Reviewer #2 (Public Review):
Authors were interested in investigating sex-specific and sex-hormone-regulated cross-tissue interactions regulated by myokines, secreted muscle hormones. Investigators used muscle tissue gene expression data from 310 people, 210 males, and 100 females, to discover sex-specific and sex-hormone-driven myokine regulation. They followed this by performing RNA-Seq on mice lacking Estrogen-1 (Esr1) in skeletal muscle. They measured gene expression in various peripheral tissues as well as skeletal muscle and discovered that myokine phenotypic differences in muscle gene expression were dominated by sex-hormone regulation, confirming the results found in the human data. When looking at peripheral tissues in the human data, cross-tissue pathway regulation was determined mostly by sex steroids such as estradiol. These …
Reviewer #2 (Public Review):
Authors were interested in investigating sex-specific and sex-hormone-regulated cross-tissue interactions regulated by myokines, secreted muscle hormones. Investigators used muscle tissue gene expression data from 310 people, 210 males, and 100 females, to discover sex-specific and sex-hormone-driven myokine regulation. They followed this by performing RNA-Seq on mice lacking Estrogen-1 (Esr1) in skeletal muscle. They measured gene expression in various peripheral tissues as well as skeletal muscle and discovered that myokine phenotypic differences in muscle gene expression were dominated by sex-hormone regulation, confirming the results found in the human data. When looking at peripheral tissues in the human data, cross-tissue pathway regulation was determined mostly by sex steroids such as estradiol. These hormonal differences did not determine muscle cell composition but instead determined cross-tissue myokine signaling. This investigation was able to replicate results from the literature, such as sex-specific myostatin-dependent muscle mass increase, and was able to reveal new genetic regulation accomplished through endocrine mechanisms. This investigation contributed majorly to the knowledge of mechanisms by which sex-specific phenomena arise, and to the interlinked field of metabolism, where sex-specific mechanisms greatly contribute. Specifically, the investigation was able to reveal putative mechanisms by which sex-specific pathological risk can be explained in hepatic inflammation. This contributed significant knowledge to the field.
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Reviewer #3 (Public Review):
Proteins that are produced and released by skeletal muscle and exert either paracrine or endocrine effects are classified as "myokines." The production and release of these myokines can be regulated by different physiological exposures like acute and long-term exercise. Two of the best described myokines are interleukine-6 (IL-6) and myostatin. Acutely exercise induced IL-6 might for example stimulate expansion of pancreatic α-cells and promote increased glucagon-like peptide 1 release from the intestine and consequently increase insulin secretion. Long-term exercise represses myostatin levels in both skeletal muscle and plasma. Myostatin has a paracrine effect on both skeletal muscle growth and glucose uptake.
In the manuscript entitle "genetic variation of human myokine signalling is dominated by …
Reviewer #3 (Public Review):
Proteins that are produced and released by skeletal muscle and exert either paracrine or endocrine effects are classified as "myokines." The production and release of these myokines can be regulated by different physiological exposures like acute and long-term exercise. Two of the best described myokines are interleukine-6 (IL-6) and myostatin. Acutely exercise induced IL-6 might for example stimulate expansion of pancreatic α-cells and promote increased glucagon-like peptide 1 release from the intestine and consequently increase insulin secretion. Long-term exercise represses myostatin levels in both skeletal muscle and plasma. Myostatin has a paracrine effect on both skeletal muscle growth and glucose uptake.
In the manuscript entitle "genetic variation of human myokine signalling is dominated by biological sex and sex hormones" by Velez et.al, the authors used human skeletal muscle gene expression data to predict common and sex-specific myokine gene regulation and cross-tissue signalling. They furthermore used male and female mice lacking estrogen receptor α (Esr1) to understand how estrogen signalling affects myokine genes expression. Finally, they investigated how muscle cellular composition affected myokine expression and cross-tissue prediction to predict novel tissue-tissue interactions.
This is an elegantly performed systems-genetics paper on the predicted human skeletal muscle secretome highlighting the importance of sex and sex hormones in regulating myokine expression and predicted cross-tissue effects. The methods used and data presented in this manuscript can serve as an important resource for other researchers in the field.
One important limitation of this study is that it is not investigating posttranscriptional and posttranslational events, secretion from skeletal muscle, or validate cross-tissue signalling to other organs. For example, myostatin has been shown to undergo posttranscriptional and posttranslational events (McMahon CD et.al., AJPEM, 2003). In other words, the fact that a gene coding for a myokine show higher expression in males than females does not necessarily mean that males will secrete more of that myokines than females. That being said, the method used to predict cross-tissue functions have previously been used to identify novel tissue-tissue communications which have been validated (Seldin MM, Cell Metabolism, 2018).
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