Skeletal muscle physiology is a critical determinant and therapeutic target for type 2 diabetes. Proteins secreted from skeletal muscle, termed myokines, allow the muscle to communicate with other key metabolic organs and several have been established as causal drivers of processes such as exercise and lipid metabolism. Yet, the genetic architecture, regulation, and functions of myokines, as well as degree of conservation of these communication circuits remains inadequately understood. In this study, we performed the first targeted genetic survey of myokine gene regulation and cross-tissue signaling in 310 humans where sex as a biological variable was emphasized. While expression levels of a majority of myokines and cell proportions within skeletal muscle showed little differences between males and females, nearly all significant cross-tissue enrichments operated in a sex-specific or hormone-dependent fashion. Estrogen signaling specifically in muscle showed striking enrichments with myokines, independent of sex-specific signaling. To define the causal roles of estrogen signaling on myokine gene expression and functions, we generated male and female mice lacking estrogen receptor α (Esr1) specifically in skeletal muscle and integrated global RNA-Sequencing with human data. These analyses highlighted mechanisms of sex-dependent myokine signaling conserved between species, such as myostatin enriched for divergent substrate utilization pathways between sexes, and GPX3 as a male-specific link between glycolytic fiber abundance and hepatic inflammation. Collectively, we provide the first genetic survey of human myokines and highlight sex and estrogen receptor signaling as critical variables when assaying myokine functions and how changes in cell composition impact other metabolic organs. This study is currently available on bioRxiv:


C. Van: None. M. Seldin: None.

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