Exercise training-induced extracellular miR-136-3p modulates glucose uptake and myogenesis through targeting of NRDC in human skeletal muscle

Mutsumi Katayama; Elena Caria; Dimitri Van Simaeys; Anna Yagüe Sanz; Romain Barrès; Kenneth Caidahl; Oscar P B Wiklander; Samir El Andaloussi; Per-Olof Berggren; Juleen R Zierath; Anna Krook

doi:10.1016/j.jshs.2025.101091

Exercise training-induced extracellular miR-136-3p modulates glucose uptake and myogenesis through targeting of NRDC in human skeletal muscle

J Sport Health Sci. 2025 Oct 3:15:101091. doi: 10.1016/j.jshs.2025.101091. Online ahead of print.

Authors

Affiliations

¹ Department of Physiology and Pharmacology, Integrative Physiology, Karolinska Institutet, Stockholm 17177, Sweden.
² Rolf Luft Research Center for Diabetes and Endocrinology, Karolinska Institutet, Stockholm 17176, Sweden.
³ Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen 2200, Denmark; Institute of Molecular and Cellular Pharmacology, Centre National de la Recherche Scientifique (CNRS) and Université Côte d'Azur, Valbonne 06560, France.
⁴ Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm 17176, Sweden.
⁵ Biomolecular and Cellular Medicine, Department of Laboratory Medicine, Karolinska Institutet, Stockholm 17177, Sweden; Karolinska ATMP Center, ANA Futura, Huddinge 14157, Sweden; Breast Center, Karolinska Comprehensive Cancer Center, Karolinska University Hospital, Stockholm 17176, Sweden.
⁶ Biomolecular and Cellular Medicine, Department of Laboratory Medicine, Karolinska Institutet, Stockholm 17177, Sweden; Department of Cellular Therapy and Allogeneic Stem Cell Transplantation, Karolinska University Hospital, Huddinge 14157, Sweden.
⁷ Rolf Luft Research Center for Diabetes and Endocrinology, Karolinska Institutet, Stockholm 17176, Sweden; Research Center for Islet Transplantation, West China Hospital, Sichuan University, Chengdu 610041, China.
⁸ Department of Physiology and Pharmacology, Integrative Physiology, Karolinska Institutet, Stockholm 17177, Sweden; Department of Molecular Medicine and Surgery, Integrative Physiology, Karolinska Institutet, Stockholm 17177, Sweden.
⁹ Department of Physiology and Pharmacology, Integrative Physiology, Karolinska Institutet, Stockholm 17177, Sweden. Electronic address: anna.krook@ki.se.

Abstract

Background: Regular physical training induces adaptive effects across multiple organ systems, highlighting the existence of inter-organ communication networks. However, the molecular mechanisms underlying both exercise-induced adaptations and organ-to-organ signaling are not fully characterized. Circulating extracellular vesicles (EVs), including exosomes, carry molecules like microRNAs (miRNAs) that may mediate tissue crosstalk. This study aimed to identify specific exercise training-responsive miRNAs that affect skeletal muscle function.

Methods: miRNA expression profiles of serum-derived EVs were analyzed in healthy young individuals before and after 3 weeks endurance exercise training. Exercise training-responsive miRNAs were then validated for a functional role in cellular metabolic processes in human myotubes.

Results: We identified several exercise training-responsive miRNAs within exosome-rich EVs in serum, including miR-136-3p. In human myotubes, miR-136-3p enhanced glucose uptake and targeted the nardilysin convertase (NRDC) gene. Transfection of miR-136-3p or silencing of NRDC induced a shift towards glycolytic metabolism in mitochondria and modulated gene expressions related to myogenesis. Pancreatic islets were identified as a potential source of miR-136-3p based on in silico analysis of gene expression and a molecular analysis of conditioned media from isolated pancreatic islets.

Conclusion: MiR-136-3p is an endurance training-responsive molecular transducer that modulates glucose metabolism and cellular proliferation in myocytes. Associated with EVs, extracellular miR-136-3p may serve as a molecular messenger to communicate islet-skeletal muscle crosstalk after exercise. Extracellular miR-136-3p may serve as a molecular messenger to communicate islet-skeletal muscle crosstalk. Our results highlight a miRNA-mediated mechanism that participates in inter-organ communication to fine tune the metabolic adaptations to exercise.

Keywords: Endurance training; Extracellular miRNA; Human skeletal muscle; Nardilycin convertase (NRDC); miR-136-3p.