2. Academic Validation
  3. microRNA-1 regulates metabolic flexibility by programming adult skeletal muscle pyruvate metabolism

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

  • Mol Metab. 2025 Aug:98:102182. doi: 10.1016/j.molmet.2025.102182.
Ahmed Ismaeel 1,  Bailey D Peck 2,  McLane M Montgomery 3,  Benjamin I Burke 1,  Jensen Goh 1,  Abigail B Franco 4,  Qin Xia 5,  Katarzyna Goljanek-Whysall 5,  Brian McDonagh 5,  Jared M McLendon 6,  Pieter J Koopmans 7,  Daniel Jacko 8,  Kirill Schaaf 8,  Wilhelm Bloch 9,  Sebastian Gehlert 10,  Kevin A Murach 7,  Kelsey H Fisher-Wellman 3,  Ryan L Boudreau 11,  Yuan Wen 12,  John J McCarthy 13
Affiliations

Affiliations

  • 1 Department of Physiology, College of Medicine, University of Kentucky, Lexington, KY, USA; Center for Muscle Biology, College of Health Sciences, University of Kentucky, Lexington, KY, USA.
  • 2 Department of Physiology, College of Medicine, University of Kentucky, Lexington, KY, USA; Center for Muscle Biology, College of Health Sciences, University of Kentucky, Lexington, KY, USA; Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, IA, USA.
  • 3 Department of Cancer Biology, Atrium Health Wake Forest Baptist Comprehensive Cancer Center, Wake Forest University School of Medicine, Winston-Salem, NC, USA.
  • 4 Department of Physiology, College of Medicine, University of Kentucky, Lexington, KY, USA; Mass Spectrometry and Proteomics Core, University of Kentucky, Lexington, KY, USA.
  • 5 Discipline of Physiology, School of Medicine, College of Medicine, Nursing, and Health Sciences, University of Galway, Galway, Ireland.
  • 6 Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, IA, USA; Department of Pharmaceutical Sciences and Experimental Therapeutics, College of Pharmacy, University of Iowa, Iowa City, IA, USA.
  • 7 Department Health, Human Performance, & Recreation, University of Arkansas, Fayetteville, AR, USA; Cell and Molecular Biology Graduate Program, University of Arkansas, Fayetteville, AR, USA.
  • 8 Institute of Cardiovascular Research and Sports Medicine, German Sport University, Cologne, Germany; Olympic Base Center, North Rhine-Westphalia/Rhineland, Cologne, Germany.
  • 9 Institute of Cardiovascular Research and Sports Medicine, German Sport University, Cologne, Germany.
  • 10 Institute of Cardiovascular Research and Sports Medicine, German Sport University, Cologne, Germany; Department for the Biosciences of Sports, Institute of Sports Science, University of Hildesheim, Hildesheim, Germany.
  • 11 Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, IA, USA.
  • 12 Department of Physiology, College of Medicine, University of Kentucky, Lexington, KY, USA; Center for Muscle Biology, College of Health Sciences, University of Kentucky, Lexington, KY, USA; Division of Biomedical Informatics, Department of Internal Medicine, College of Medicine, University of Kentucky, Lexington, KY, USA.
  • 13 Department of Physiology, College of Medicine, University of Kentucky, Lexington, KY, USA; Center for Muscle Biology, College of Health Sciences, University of Kentucky, Lexington, KY, USA. Electronic address: jjmcca2@uky.edu.
PMID: 40490136 DOI: 10.1016/j.molmet.2025.102182
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.

Keywords

Aerobic glycolysis; MCT4; PKM; Resistance training; VB124; eCLIP-seq.

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