microRNA-1 regulates metabolic flexibility by programming adult skeletal muscle pyruvate metabolism

IF 7 2区医学 Q1 ENDOCRINOLOGY & METABOLISM

Molecular Metabolism Pub Date : 2025-06-07 DOI:10.1016/j.molmet.2025.102182

Ahmed Ismaeel , Bailey D. Peck , McLane M. Montgomery , Benjamin I. Burke , Jensen Goh , Abigail B. Franco , Qin Xia , Katarzyna Goljanek-Whysall , Brian McDonagh , Jared M. McLendon , Pieter J. Koopmans , Daniel Jacko , Kirill Schaaf , Wilhelm Bloch , Sebastian Gehlert , Kevin A. Murach , Kelsey H. Fisher–Wellman , Ryan L. Boudreau , Yuan Wen , John J. McCarthy

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引用次数: 0

Abstract

Objective

Metabolic flexibility refers to the ability of tissues to adjust cellular fuel choice in response to conditional changes in metabolic demand and activity. A loss of metabolic flexibility is a defining feature of various diseases and cellular dysfunction. This study investigated the role of microRNA-1 (miR-1), the most abundant microRNA in skeletal muscle, in maintaining whole-body metabolic flexibility.

Methods

We used an inducible, skeletal muscle-specific knockout (KO) mouse model to examine miR-1 function. Argonaute 2 enhanced crosslinking and immunoprecipitation sequencing (AGO2 eCLIP-seq) and RNA-seq analyses identified miR-1 target genes. Metabolism was investigated using metabolomics, proteomics, and comprehensive bioenergetic and activity phenotyping. Corroborating information was provided from cell culture, C. elegans, and exercised human muscle tissue.

Results

miR-1 KO mice demonstrated loss of diurnal oscillations in whole-body respiratory exchange ratio and higher fasting blood glucose. For the first time, we identified bona fide miR-1 target genes in adult skeletal muscle that regulated pyruvate metabolism through mechanisms including the alternative splicing of pyruvate kinase (Pkm). The maintenance of metabolic flexibility by miR-1 was necessary for sustained endurance activity in mice and in C. elegans. Loss of metabolic flexibility in the miR-1 KO mouse was rescued by pharmacological inhibition of the miR-1 target, monocarboxylate transporter 4 (MCT4), which redirects glycolytic carbon flux toward oxidation. The physiological down-regulation of miR-1 in response to hypertrophic stimuli caused a similar metabolic reprogramming necessary for muscle cell growth.

Conclusions

These data identify a novel post-transcriptional mechanism of whole-body metabolism regulation mediated by a tissue-specific miRNA.

Abstract Image

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microRNA-1通过编程成人骨骼肌丙酮酸代谢调节代谢灵活性。

代谢灵活性是指组织根据代谢需求和活动的条件变化调整细胞燃料选择的能力。代谢灵活性的丧失现在被认为是各种疾病和细胞功能障碍的一个决定性特征。在这项研究中，使用可诱导的骨骼肌特异性敲除（KO）小鼠，我们发现骨骼肌中最丰富的microRNA-1 （miR-1）是维持全身代谢灵活性所必需的。miR-1 KO小鼠的全身呼吸交换比的昼夜振荡丧失和更高的空腹血糖证明了这一点。Argonaute 2增强交联和免疫沉淀测序（AGO2 ecip -seq）和RNA-seq分析首次鉴定出成人骨骼肌中调节丙酮酸代谢的真正的miR-1靶基因。结合骨骼肌蛋白质组学和代谢组学的综合生物能量表型分析表明，miR-1通过丙酮酸激酶（Pkm）的选择性剪接等机制调节丙酮酸代谢，从而维持代谢灵活性。miR-1 KO小鼠代谢灵活性的丧失可以通过药物抑制miR-1靶点，单羧酸转运蛋白4 （MCT4）来恢复，MCT4将糖酵解碳通量重新导向氧化。miR-1维持代谢灵活性对于小鼠和秀丽隐杆线虫的持续耐力活动是必要的。在人类和小鼠中，miR-1的生理下调是对肥厚刺激的反应，引起了肌肉细胞生长所必需的类似代谢重编程。综上所述，这些数据确定了一种由组织特异性miRNA介导的全身代谢调节的新型转录后机制。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Molecular Metabolism ENDOCRINOLOGY & METABOLISM-

CiteScore

14.50

自引率

2.50%

发文量

219

审稿时长

43 days

期刊介绍： Molecular Metabolism is a leading journal dedicated to sharing groundbreaking discoveries in the field of energy homeostasis and the underlying factors of metabolic disorders. These disorders include obesity, diabetes, cardiovascular disease, and cancer. Our journal focuses on publishing research driven by hypotheses and conducted to the highest standards, aiming to provide a mechanistic understanding of energy homeostasis-related behavior, physiology, and dysfunction. We promote interdisciplinary science, covering a broad range of approaches from molecules to humans throughout the lifespan. Our goal is to contribute to transformative research in metabolism, which has the potential to revolutionize the field. By enabling progress in the prognosis, prevention, and ultimately the cure of metabolic disorders and their long-term complications, our journal seeks to better the future of health and well-being.