Matthew P Bubak, Shivani N. Mann, Agnieszka K. Borowik, Atul Pranay, Albert Batushansky, Ivo Vieira de Sousa Neto, Samim A. Ali Mondal, Stephen M Doidge, Arik Davidyan, Marcelina M Szczygiel, Frederick F. Peelor III, Sandra Rigsby, Matle E Broomfield, Charles I. Lacy, Heather C. Rice, Michael B. Stout, Benjamin F. Miller

17α-estradiol Alleviates High-Fat Diet-Induced Inflammatory and Metabolic Dysfunction in Skeletal Muscle of Male and Female Mice

  • Physiology (medical)
  • Physiology
  • Endocrinology, Diabetes and Metabolism

17α-estradiol (17α-E2) is a naturally occurring non-feminizing diastereomer of 17β-estradiol that has lifespan extending effects in rodent models. To date studies of the systemic and tissue-specific benefits of 17α-E2 have largely focused on liver, brain, and white adipose tissue with far less focus on skeletal muscle. Skeletal muscle has an important role in metabolic and age-related disease. Therefore, this study aimed to determine if 17α-E2 treatment has positive, tissue-specific effects in skeletal muscle during a high fat feeding. We hypothesized that male, but not female, mice, would benefit from 17α-E2 treatment during a HFD with changes in the mitochondrial proteome to support lipid oxidation and subsequent reductions in DAG and ceramide content. To test this hypothesis, we used a multi-omics approach to determine changes in lipotoxic lipid intermediates, metabolites, and proteins related to metabolic homeostasis. Unexpectedly, we found that 17α-E2 had marked but different beneficial effects within each sex. In male mice, we show that 17α-E2 alleviates HFD-induced metabolic detriments of skeletal muscle by reducing the accumulation of diacylglycerol (DAGs) and ceramides, inflammatory cytokine levels, and altered the abundance of most of the proteins related to lipolysis and beta-oxidation. Similar to male mice, 17α-E2 treatment reduced fat mass while protecting muscle mass in female mice but had little muscle inflammatory cytokine levels. While female mice were resistant to HFD induced changes in DAGs, 17α-E2 treatment induced the upregulation six DAG species. In female mice, 17α-E2 treatment changed the relative abundance of proteins involved in lipolysis, beta-oxidation, as well as structural and contractile proteins but to a smaller extent than male mice. These data demonstrate metabolic benefits of 17α-E2 in skeletal muscle of male and female mice and contribute to the growing literature of the use of 17α-E2 for multi-tissue healthspan benefits.

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