Bubak Matthew P, Mann Shivani N, Borowik Agnieszka K, Pranay Atul, Batushansky Albert, Mondal Samim Ali, Diodge Stephen M, Davidyan Arik, Szczygiel Marcelina M, Peelor Fredrick R, Rigsby Sandra, Broomfield Matle, Lacy Charles I, Rice Heather C, Stout Michael B, Miller Benjamin F
bioRxiv. 2023 Jun 15:2023.05.30.542870. doi: 10.1101/2023.05.30.542870.
Skeletal muscle has a central role in maintaining metabolic homeostasis. 17α-estradiol (17α-E2), a naturally-occurring non-feminizing diastereomer of 17β-estradiol that demonstrates efficacy for improving metabolic outcomes in male, but not female, mice. Despite several lines of evidence showing that 17α-E2 treatment improves metabolic parameters in middle-aged obese and old male mice through effects in brain, liver, and white adipose tissue little is known about how 17α-E2 alters skeletal muscle metabolism, and what role this may play in mitigating metabolic declines. Therefore, this study aimed to determine if 17α-E2 treatment improves metabolic outcomes in skeletal muscle from obese male and female mice following chronic high fat diet (HFD) administration. We hypothesized that male, but not female, mice, would benefit from 17α-E2 treatment during HFD. To test this hypothesis, we used a multi-omics approach to determine changes in lipotoxic lipid intermediates, metabolites, and proteins related to metabolic homeostasis. 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 reduced the abundance of most of the proteins related to lipolysis and beta-oxidation. In contrast to males, 17α-E2 treatment in female mice had little effect on the DAGs and ceramides content, muscle inflammatory cytokine levels, or changes to the relative abundance of proteins involved in beta-oxidation. These data support to the growing evidence that 17α-E2 treatment could be beneficial for overall metabolic health in male mammals.
骨骼肌在维持代谢稳态中起着核心作用。17α-雌二醇（17α-E2）是17β-雌二醇的一种天然存在的非女性化非对映异构体，已证明其对改善雄性而非雌性小鼠的代谢结果有效。尽管有多项证据表明，17α-E2治疗可通过对脑、肝和白色脂肪组织的作用改善中年肥胖和老年雄性小鼠的代谢参数，但对于17α-E2如何改变骨骼肌代谢以及这在减轻代谢衰退中可能发挥何种作用知之甚少。因此，本研究旨在确定17α-E2治疗是否能改善长期高脂饮食（HFD）喂养的肥胖雄性和雌性小鼠骨骼肌的代谢结果。我们假设，在高脂饮食期间，雄性而非雌性小鼠会从17α-E2治疗中受益。为了验证这一假设，我们采用了多组学方法来确定与代谢稳态相关的脂毒性脂质中间体、代谢物和蛋白质的变化。在雄性小鼠中，我们发现17α-E2通过减少二酰甘油（DAGs）和神经酰胺的积累、炎症细胞因子水平，并降低与脂肪分解和β-氧化相关的大多数蛋白质的丰度，减轻了高脂饮食诱导的骨骼肌代谢损害。与雄性小鼠相反，17α-E2治疗对雌性小鼠的DAGs和神经酰胺含量、肌肉炎症细胞因子水平或参与β-氧化的蛋白质相对丰度变化几乎没有影响。这些数据支持了越来越多的证据，即17α-E2治疗可能对雄性哺乳动物的整体代谢健康有益。
