Musclin is an activity-stimulated myokine that enhances physical endurance
Open accessAbstract
Exercise remains the most effective way to promote physical and metabolic wellbeing, but molecular mechanisms underlying exercise tolerance and its plasticity are only partially understood. In this study we identify musclin-a peptide with high homology to natriuretic peptides (NP)-as an exercise-responsive myokine that acts to enhance exercise capacity in mice. We use human primary myoblast culture and in vivo murine models to establish that the activity-related production of musclin is driven by Ca(2+)-dependent activation of Akt1 and the release of musclin-encoding gene (Ostn) transcription from forkhead box O1 transcription factor inhibition. Disruption of Ostn and elimination of musclin secretion in mice results in reduced exercise tolerance that can be rescued by treatment with recombinant musclin. Reduced exercise capacity in mice with disrupted musclin signaling is associated with a trend toward lower levels of plasma atrial NP (ANP) and significantly smaller levels of cyclic guanosine monophosphate (cGMP) and peroxisome proliferator-activated receptor gamma coactivator 1-α in skeletal muscles after exposure to exercise. Furthermore, in agreement with the established musclin ability to interact with NP clearance receptors, but not with NP guanyl cyclase-coupled signaling receptors, we demonstrate that musclin enhances cGMP production in cultured myoblasts only when applied together with ANP. Elimination of the activity-related musclin-dependent boost of ANP/cGMP signaling results in significantly lower maximum aerobic capacity, mitochondrial protein content, respiratory complex protein expression, and succinate dehydrogenase activity in skeletal muscles. Together, these data indicate that musclin enhances physical endurance by promoting mitochondrial biogenesis.
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Musclin is an exercise-induced factor promoting skeletal muscle mitochondrial biogenesis in mice.
“Musclin has been identified as an exercise-induced factor (64) promoting skeletal muscle mitochondrial biogenesis in mice (65).”
From Muscle–Organ Crosstalk: The Emerging Roles of Myokines (2020) · cites this paper as [65]
In skeletal muscle, myocytes secrete factors such as lactate, musclin and myostatin that link exercise to mitochondrial biogenesis and myocyte substrate utilization.
“in skeletal muscle, myocytes secrete factors such as lactate41, musclin43 and myostatin44 that couple exercise to changes in mitochondrial biogenesis and myocyte substrate utilization.”
From Exerkines in health, resilience and disease (2022) · cites this paper as [43]
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- Authors
- Subbotina, E., Sierra, A., Zhu, Z., Gao, Z., Koganti, S. R. K., Reyes, S., Stepniak, E., Walsh, S. A., Acevedo, M. R., Perez-Terzic, C. M., Hodgson-Zingman, D. M., & Zingman, L. V.
- Affiliations
- University of Iowa (US)
- Mayo Clinic (US)
- Department of Physical Medicine and Rehabilitation, Mayo Clinic, Rochester, MN 55905;
- Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, IA 52242;
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2015-12-14
- Volume
- 112
- Issue
- 52
- Pages
- 16042-16047
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC4702977
- OpenAlex
- W2221507346
- Cited by
- 198
- References
- 43
- Citations by year
- 2026: 25 · 2025: 24 · 2024: 20 · 2023: 24 · 2022: 15 · 2021: 22 · 2020: 16 · 2019: 13 · 2018: 13 · 2017: 11 · 2016: 15
- FWCI
- 25.53
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- HHS | National Institutes of Health (DK092412, HL093368, HL113089)
- U.S. Department of Veterans Affairs (1I0BX000718)
- Fraternal Order of Eagles (Pilot Grant)
- Topics
- Health Sciences › Medicine › Complementary and alternative medicine › Cardiovascular and exercise physiology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Muscle Physiology and Disorders
- Health Sciences › Medicine › Rehabilitation › Exercise and Physiological Responses
- Keywords
- musclin, myokines, exercise tolerance, physical endurance, natriuretic peptides, atrial natriuretic peptide, cGMP signaling, FOXO1, AKT1, mitochondrial biogenesis, skeletal muscle, maximal aerobic capacity, succinate dehydrogenase, electron transport chain
- MeSH terms
- Calcimycin, Forkhead Box Protein O1, Animals, Calcium, Cells, Cultured, Female, Cyclic GMP, Humans, Male, Mice, Inbred C57BL, Muscle Proteins, Atrial Natriuretic Factor, Phosphorylation, Physical Conditioning, Animal, Transcription Factors, Blotting, Western, Signal Transduction, Mice, Knockout, Muscle, Skeletal, Myoblasts, Proto-Oncogene Proteins c-akt, Forkhead Transcription Factors, Calcium Ionophores
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