Skeletal muscle Rac1 mediates exercise training adaptations towards muscle glycogen resynthesis and protein synthesis
Long-term exercise training elicits tremendous health benefits; however, the molecular understanding is incomplete and identifying therapeutic targets has been challenging. Rho GTPases are among the most regulated groups of proteins after exercise in human skeletal muscle, yet, unexplored candidates for mediating the effects of exercise training. We found that the Rho GTPase Rac1 was activated acutely after multiple exercise modalities in human skeletal muscle. Loss of Rac1 specifically in muscle attenuated contraction-induced muscle protein synthesis, diminished improvements in running capacity, and prevented muscle hypertrophy after exercise training in mice. Additionally, Ncf1∗ mice revealed that Rac1 regulated glycogen resynthesis via a NOX2-dependent mechanism. Molecularly, Rac1 was required for contraction-induced p38MAPK signaling towards HSP27, MNK1, and CREB phosphorylation. In vivo muscle-targeted overexpression of a hyperactive Rac1-mutant elevated reactive oxidant species production during exercise but did not affect muscle mass. Using mass spectrometry-based proteomics, we found that loss or gain of Rac1 muscle protein affected pathways related to cytoskeleton organization, muscle adaptation, and large ribosomal subunits. Thus, skeletal muscle Rac1 mediates both molecular and functional adaptation to exercise training.
Authors
- Jonas R. Knudsen (ORCID: https://orcid.org/0000-0002-5471-491X)
- Rikard Holmdahl (ORCID: https://orcid.org/0000-0002-4969-2576)
- Erik A. Richter (ORCID: https://orcid.org/0000-0002-6850-3056)
- Paul Gregorevic (ORCID: https://orcid.org/0000-0002-7418-8945)
- Thomas E. Jensen (ORCID: https://orcid.org/0000-0001-6139-8268)
- Hongwei Qian (ORCID: https://orcid.org/0000-0002-5991-6860)
- Jonathan R. Davey
- Steffen H. Raun (ORCID: https://orcid.org/0000-0003-2050-505X)
- Bente Kiens (ORCID: https://orcid.org/0000-0001-5705-5625)
- Lykke Sylow (ORCID: https://orcid.org/0000-0003-0905-5932)
- Carlos Henríquez‐Olguín (ORCID: https://orcid.org/0000-0002-9315-9365)
- Christian S. Carl (ORCID: https://orcid.org/0000-0002-9551-5837)
- Lisbeth L. V. Møller (ORCID: https://orcid.org/0000-0003-1885-0102)
- Ana Varela Coelho (ORCID: https://orcid.org/0000-0002-6143-4203)
- Emma Frank (ORCID: https://orcid.org/0000-0001-8065-2030)
- Atul S. Deshmukh (ORCID: https://orcid.org/0000-0002-2278-1843)
- Nicoline R. Andersen (ORCID: https://orcid.org/0000-0002-1512-2727)
- Christian T. Voldstedlund (ORCID: https://orcid.org/0000-0002-6368-8995)
- Mona Sadek Ali (ORCID: https://orcid.org/0000-0003-1152-3256)
- Farina Schlabs
- N Hähn
Institutions
- University of Copenhagen (DK)
- The University of Melbourne (AU)
- Novo Nordisk Foundation (DK)
- Karolinska Institutet (SE)
- Finis Terrae University (CL)
Publication Details
- Journal
- Redox Biology
- Published
- 2025-08-28
- DOI
- https://doi.org/10.1016/j.redox.2025.103844
- Citations
- 5
- Primary Topic
- Muscle metabolism and nutrition
- Type
- article
- Field-Weighted Citation Impact
- 5.76
Funders
- Danish Diabetes Academy
- Carlsbergfondet
- Gentofte Hospital
- Lundbeckfonden
- Vetenskapsrådet
- Faculty of Health and Medical Sciences, University of Western Australia
- Novo Nordisk Fonden
- Danmarks Frie Forskningsfond
- Bispebjerg Hospital
- Det Sundhedsvidenskabelige Fakultet, Københavns Universitet