Lactate as a metabolic-epigenetic signal linking high-intensity interval training (HIIT) to miRNA-Centered remodeling of the skeletal muscle methylome and transcriptome

  • Redox Biol. 2025 Dec:88:103943. doi: 10.1016/j.redox.2025.103943.
Lei Zhou  1 ,  Soroosh Mozaffaritabar  1 ,  Kumpei Tanisawa  2 ,  Takuji Kawamura  1 ,  Mitsuru Higuchi  2 ,  Istvan Boldogh  3 ,  Xueqing Ba  4 ,  Sataro Goto  1 ,  George Brooks  5 ,  Yaodong Gu  6 ,  Zsolt Radák  7
Affiliations
  • 1. Research Institute of Molecular Exercise Science, Hungarian University of Sports Science, Budapest, H-1123, Hungary.
  • 2. Faculty of Sport Sciences, Waseda University, Tokorozawa, Japan.
  • 3. Department of Microbiology and Immunology, University of Texas Medical Branch at Galveston, Galveston, TX, 77555, USA.
  • 4. Division of Human Health, Key Laboratory of Molecular Epigenetics of Ministry of Education, Northeast Normal University, Changchun, 130024, China.
  • 5. Department of Integrative Biology, University of California, Berkeley, CA, USA.
  • 6. Faculty of Sport Science, Ningbo University, Ningbo, 315211, China.
  • 7. Research Institute of Molecular Exercise Science, Hungarian University of Sports Science, Budapest, H-1123, Hungary; Faculty of Sport Sciences, Waseda University, Tokorozawa, Japan; Faculty of Sport Science, Ningbo University, Ningbo, 315211, China. Electronic address: [email protected].
PMID: 41314005 DOI: 10.1016/j.redox.2025.103943
Abstract

Background: Lactate, a key exercise-derived metabolite and exerkine, is increasingly recognized as a metabolic-epigenetic signal, yet whether lactate and its transport directly shape skeletal-muscle epigenetic and transcriptional adaptations to exercise remains unclear.

Methods: Young male mice underwent six-week interventions: Control, lactate administration, high intensity interval training (HIIT), Monocarboxylate Transporter isoforms 1 and 2 (MCT1/2) inhibition, or HIIT plus inhibition. Gastrocnemius muscle was profiled by DNA methylation arrays, mRNA and miRNA-seq, together with analyses of signaling proteins, metabolites, and running performance.

Results: Exogenous lactate and HIIT each elicited broad, site-specific remodeling of the skeletal muscle methylome and transcriptome with substantial overlap at promoter CpGs and differentially expressed genes. Promoter methylation changes showed weak coupling to steady-state mRNA, whereas integrative analyses revealed robust anti-directional miRNA-mRNA networks and included numerous chromatin and epigenetic regulators, identifying a lactate-driven, miRNA-centered axis. At the protein level, lactate increased TET2/DNMT3A and activated signaling involved in satellite-cell activation, angiogenesis, and AKT-S6 axis, accompanied by reciprocal miRNA-mRNA pairs. HIIT increased TET1/2 and DNMT3A, reduced DNMT3B, and uniquely enhanced mitochondrial/antioxidant signaling. Pharmacologic MCT1/2 blockade abrogated HIIT-induced methylome and miRNA remodeling and blunted transcriptomic and protein adaptations, demonstrating that intact lactate flux is required for exercise-induced epigenetic reprogramming. Despite molecular convergence, chronic lactate did not improve running performance, suggesting that lactate is necessary, but not sufficient for the full physiological benefits of HIIT.

Conclusions: These data support a lactate-miRNA-transcriptome/epigenome interplay that links metabolic perturbation to gene regulation in skeletal muscle. Using an integrated multi-omics approach, we propose a mechanistic framework for future studies targeting metabolic-epigenetic signaling in both physiology and pathology.

Keywords
DNA methylation; Epigenetic regulation; High-intensity interval training (HIIT); Lactate; MCT1; MCT2; Skeletal muscle adaptation; Transcriptome; microRNA.
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