Journal article
microRNA-1 Regulates Metabolic Flexibility by Programming Adult Skeletal Muscle Pyruvate Metabolism
Molecular metabolism (Germany), Vol.98, 102182
08/2025
DOI: 10.1016/j.molmet.2025.102182
PMCID: PMC12214129
PMID: 40490136
Abstract
Metabolic flexibility refers to the ability of a tissue to adjust cellular fuel choice in response to conditional changes in metabolic demand and activity. A loss of metabolic flexibility is now recognized as a defining feature of various diseases and cellular dysfunction. In this study, using an inducible, skeletal muscle-specific knockout (KO) mouse, we found microRNA-1 (miR-1), the most abundant microRNA (miRNA) in skeletal muscle, was necessary to maintain whole-body metabolic flexibility. This was demonstrated by a loss of diurnal oscillations in whole-body respiratory exchange ratio and higher fasting blood glucose in miR-1 KO mice. Argonaute 2 enhanced crosslinking and immunoprecipitation sequencing (AGO2 eCLIP-seq) and RNA-seq analyses identified, for the first time, bona fide miR-1 target genes in adult skeletal muscle that regulated pyruvate metabolism. Comprehensive bioenergetic phenotyping combined with skeletal muscle proteomics and metabolomics showed that miR-1 was necessary to maintain metabolic flexibility by regulating pyruvate metabolism through mechanisms including the alternative splicing of pyruvate kinase (Pkm). The 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 maintenance of metabolic flexibility by miR-1 was necessary for sustained endurance activity in mice and in C. elegans. The physiological down-regulation of miR-1 in response to a hypertrophic stimulus in both humans and mice caused a similar metabolic reprogramming necessary for muscle cell growth. Taken together, these data identify a novel post-transcriptional mechanism of whole-body metabolism regulation mediated by a tissue-specific miRNA.
Details
- Title: Subtitle
- microRNA-1 Regulates Metabolic Flexibility by Programming Adult Skeletal Muscle Pyruvate Metabolism
- Creators
- Ahmed Ismaeel - University of KentuckyBailey D Peck - University of KentuckyMcLane M Montgomery - Wake Forest UniversityBenjamin I Burke - University of KentuckyJensen Goh - University of KentuckyAbigail B Franco - University of KentuckyQin Xia - Ollscoil na Gaillimhe – University of GalwayKatarzyna Goljanek-Whysall - Ollscoil na Gaillimhe – University of GalwayBrian McDonagh - Ollscoil na Gaillimhe – University of GalwayJared M McLendon - University of IowaPieter J Koopmans - University of Arkansas at FayettevilleDaniel Jacko - German Sport University CologneKirill Schaaf - German Sport University CologneWilhelm Bloch - German Sport University CologneSebastian Gehlert - German Sport University CologneKevin A Murach - University of Arkansas at FayettevilleKelsey H Fisher-Wellman - Wake Forest UniversityRyan L Boudreau - University of IowaYuan Wen - University of KentuckyJohn J McCarthy - University of Kentucky
- Resource Type
- Journal article
- Publication Details
- Molecular metabolism (Germany), Vol.98, 102182
- DOI
- 10.1016/j.molmet.2025.102182
- PMID
- 40490136
- PMCID
- PMC12214129
- NLM abbreviation
- Mol Metab
- ISSN
- 2212-8778
- eISSN
- 2212-8778
- Publisher
- ELSEVIER; AMSTERDAM
- Grant note
- National Institutes of Health grants from the National Institute on Aging: R01AG069909, R00AG063994 National Heart, Lung and Blood Institute: HL144717, HL150557
This work was supported by National Institutes of Health grants from the National Institute on Aging (R01AG069909 to J.J.M. and R00AG063994 to K.A.M.) and the National Heart, Lung and Blood Institute (HL144717 and HL150557 to R.L.B.).
- Language
- English
- Electronic publication date
- 06/07/2025
- Date published
- 08/2025
- Academic Unit
- Iowa Neuroscience Institute; Pharmaceutical Sciences and Experimental Therapeutics; Cardiovascular Medicine; Fraternal Order of Eagles Diabetes Research Center; Internal Medicine
- Record Identifier
- 9984829886302771
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