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

Abstract

Skeletal muscle plays an integral role in coordinating physiologic 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 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.

Dysregulated systemic metabolism in a Down syndrome mouse model

“…Given the significant changes in systemic metabolism and the differential patterns of gene expressions across tissues observed in Ts65Dn mice, we sought to elucidate metabolic mechanisms conserved in humans and prioritize putative central driver genes. To accomplish this, we leveraged publicly available datasets of human cross-tissue RNA-sequencing [ 96 ] where correlated patterns of specific gene sets could be used to inform metabolic signaling between tissues [ [106] , [107] , [108] , [109] ]. Analysis of genetic correlation structure of Ts65Dn DEGs showed clustering patterns consistent with gene regulation specific to individual tissues ( Figure 10 B).…”

Feeding Neurons Integrate Metabolic and Reproductive States in Mice

“…To determine if TN SST neurons communicate with adipose tissue or vice versa , we used a co-correlation analysis method based on genetic variation. High expressing genes from TN SST neurons (based on counts > glial fibrillary acidic protein, GFAP, expression) were used as the “target” pathways, where human orthologues within the GTEx database (Lonsdale et al, 2013) and subjected to cross-tissue genetic co-correlational analyses (Seldin et al, 2018; Velez et al, 2022) (Figure 5A). As previous data indicated that TN SST neuron responsivity to metabolic cues might be localized to periods of higher circulating estradiol (Figure 2D) and TN SST may be able to directly sense circulating estradiol levels (Figure 4), individuals in the GTEx database were binned into groups with either “high” or “low” circulating estradiol levels via weighted aggregation of pan-tissue z-scores corresponding to estrogen responsive gene expression (Sup Fig 3).…”

“…Volcano plots were produced by the custom R function “deseq_volcano_plot_gs()” available through the following package: http://github.com/jevanveen/ratplots. Raw reads of the RNA sequencing data were also examined for hypothalamus-peripheral tissue co-correlations across stomach, small intestine, skeletal muscle, visceral fat, and subcutaneous fat as hypothalamic reads using the GTEx database as previously described (Seldin et al, 2018; Velez et al, 2022). In addition, estrogen-responsive genes used to infer “low” vs “high estrogen signaling were gathered from: https://www.gsea-msigdb.org/gsea/msigdb/cards/HALLMARK_ESTROGEN_RESPONSE_EARLY.html.…”

Causal effects of serum sex hormone binding protein levels on the risk of amyotrophic lateral sclerosis: a mendelian randomization study

“…Estrogens have been reported to exert neuroprotective effects through their action on cognate nuclear and membrane receptors ( 39 ). In the brain, sex hormones might affect a variety of signaling pathways, including catecholaminergic and acetylcholine pathways, which regulate cognition, motor, emotion, and other functions ( 41 ). Correspondingly, sex hormone receptors can induce various signaling cascades that mediate sex differences in neurodegenerative disorders ( 42 ).…”