Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Chemical Physiology, The Scripps Research Institute, La Jolla, CA 92037, USA.
Mol Metab. 2023 Feb;68:101670. doi: 10.1016/j.molmet.2023.101670. Epub 2023 Jan 13.
Skeletal muscle oxidative capacity is central to physical activity, exercise capacity and whole-body metabolism. The three estrogen-related receptors (ERRs) are regulators of oxidative metabolism in many cell types, yet their roles in skeletal muscle remain unclear. The main aim of this study was to compare the relative contributions of ERRs to oxidative capacity in glycolytic and oxidative muscle, and to determine defects associated with loss of skeletal muscle ERR function.
We assessed ERR expression, generated mice lacking one or two ERRs specifically in skeletal muscle and compared the effects of ERR loss on the transcriptomes of EDL (predominantly glycolytic) and soleus (oxidative) muscles. We also determined the consequences of the loss of ERRs for exercise capacity and energy metabolism in mice with the most severe loss of ERR activity.
ERRs were induced in human skeletal muscle in response to an exercise bout. Mice lacking both ERRα and ERRγ (ERRα/γ dmKO) had the broadest and most dramatic disruption in skeletal muscle gene expression. The most affected pathway was "mitochondrial function", in particular Oxphos and TCA cycle genes, and transcriptional defects were more pronounced in the glycolytic EDL than the oxidative soleus. Mice lacking ERRβ and ERRγ, the two isoforms expressed highly in oxidative muscles, also exhibited defects in lipid and branch chain amino acid metabolism genes, specifically in the soleus. The pronounced disruption of oxidative metabolism in ERRα/γ dmKO mice led to pale muscles, decreased oxidative capacity, histochemical patterns reminiscent of minicore myopathies, and severe exercise intolerance, with the dmKO mice unable to switch to lipid utilization upon running. ERRα/γ dmKO mice showed no defects in whole-body glucose and energy homeostasis.
Our findings define gene expression programs in skeletal muscle that depend on different combinations of ERRs, and establish a central role for ERRs in skeletal muscle oxidative metabolism and exercise capacity. Our data reveal a high degree of functional redundancy among muscle ERR isoforms for the protection of oxidative capacity, and show that ERR isoform-specific phenotypes are driven in part, but not exclusively, by their relative levels in different muscles.
骨骼肌的氧化能力是体力活动、运动能力和全身代谢的核心。三种雌激素相关受体（ERRs）是许多细胞类型氧化代谢的调节剂，但它们在骨骼肌中的作用尚不清楚。本研究的主要目的是比较 ERRs 对糖酵解和氧化肌肉氧化能力的相对贡献，并确定与骨骼肌 ERR 功能丧失相关的缺陷。
我们评估了 ERR 的表达，生成了专门在骨骼肌中缺失一种或两种 ERR 的小鼠，并比较了 ERR 缺失对 EDL（主要是糖酵解）和比目鱼肌（氧化）肌肉转录组的影响。我们还确定了 ERR 活性丧失最严重的小鼠的运动能力和能量代谢的后果。
ERRs 在人类骨骼肌中对运动发作有反应。缺乏两种 ERRα 和 ERRγ（ERRα/γ dmKO）的小鼠在骨骼肌基因表达中表现出最广泛和最显著的破坏。受影响最严重的途径是“线粒体功能”，特别是 Oxphos 和 TCA 循环基因，并且在糖酵解的 EDL 中比在氧化的比目鱼肌中转录缺陷更为明显。缺乏 ERRβ 和 ERRγ，即高度表达于氧化肌肉的两种同工型，也表现出脂质和支链氨基酸代谢基因的缺陷，特别是在比目鱼肌中。ERRα/γ dmKO 小鼠氧化代谢的显著破坏导致肌肉苍白、氧化能力下降、组织化学模式类似于微小核心肌病，并导致严重的运动不耐受，dmKO 小鼠在跑步时无法切换到脂质利用。ERRα/γ dmKO 小鼠在全身葡萄糖和能量稳态方面没有缺陷。
我们的发现定义了依赖于不同 ERR 组合的骨骼肌基因表达程序，并确立了 ERR 在骨骼肌氧化代谢和运动能力中的核心作用。我们的数据揭示了肌肉 ERR 同工型之间存在高度的功能冗余，以保护氧化能力，并且表明 ERR 同工型特异性表型部分但不是完全由它们在不同肌肉中的相对水平驱动。
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