Genetic variation of putative myokine signaling is dominated by biological 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 understa...
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2022-04-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/76887 |
| _version_ | 1811252214622060544 |
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| author | Leandro M Velez Cassandra Van Timothy Moore Zhenqi Zhou Casey Johnson Andrea L Hevener Marcus M Seldin |
| author_facet | Leandro M Velez Cassandra Van Timothy Moore Zhenqi Zhou Casey Johnson Andrea L Hevener Marcus M Seldin |
| author_sort | Leandro M Velez |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-12T16:31:31Z |
| format | Article |
| id | doaj.art-dea551aef1554c2d83f6b94ccf110c2b |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-12T16:31:31Z |
| publishDate | 2022-04-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-dea551aef1554c2d83f6b94ccf110c2b2022-12-22T03:25:09ZengeLife Sciences Publications LtdeLife2050-084X2022-04-011110.7554/eLife.76887Genetic variation of putative myokine signaling is dominated by biological sex and sex hormonesLeandro M Velez0https://orcid.org/0000-0001-8371-2633Cassandra Van1https://orcid.org/0000-0002-8434-0189Timothy Moore2Zhenqi Zhou3Casey Johnson4Andrea L Hevener5https://orcid.org/0000-0003-1508-4377Marcus M Seldin6https://orcid.org/0000-0001-8026-4759Department of Biological Chemistry, University of California, Irvine, Irvine, United States; Center for Epigenetics and Metabolism, University of California Irvine, Irvine, United StatesDepartment of Biological Chemistry, University of California, Irvine, Irvine, United States; Center for Epigenetics and Metabolism, University of California Irvine, Irvine, United StatesDepartment of Medicine, Division of Cardiology, David Geffen School of Medicine at UCLA, Los Angeles, United StatesDepartment of Medicine, Division of Endocrinology, Diabetes and Hypertension, David Geffen School of Medicine at UCLA, Los Angeles, United StatesDepartment of Biological Chemistry, University of California, Irvine, Irvine, United States; Center for Epigenetics and Metabolism, University of California Irvine, Irvine, United StatesDepartment of Medicine, Division of Endocrinology, Diabetes and Hypertension, David Geffen School of Medicine at UCLA, Los Angeles, United States; Iris Cantor-UCLA Women’s Health Research Center, David Geffen School of Medicine at UCLA, Los Angeles, United StatesDepartment of Biological Chemistry, University of California, Irvine, Irvine, United States; Center for Epigenetics and Metabolism, University of California Irvine, Irvine, United StatesSkeletal 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.https://elifesciences.org/articles/76887myokineendocrinologysystems geneticsphysiology |
| spellingShingle | Leandro M Velez Cassandra Van Timothy Moore Zhenqi Zhou Casey Johnson Andrea L Hevener Marcus M Seldin Genetic variation of putative myokine signaling is dominated by biological sex and sex hormones eLife myokine endocrinology systems genetics physiology |
| title | Genetic variation of putative myokine signaling is dominated by biological sex and sex hormones |
| title_full | Genetic variation of putative myokine signaling is dominated by biological sex and sex hormones |
| title_fullStr | Genetic variation of putative myokine signaling is dominated by biological sex and sex hormones |
| title_full_unstemmed | Genetic variation of putative myokine signaling is dominated by biological sex and sex hormones |
| title_short | Genetic variation of putative myokine signaling is dominated by biological sex and sex hormones |
| title_sort | genetic variation of putative myokine signaling is dominated by biological sex and sex hormones |
| topic | myokine endocrinology systems genetics physiology |
| url | https://elifesciences.org/articles/76887 |
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