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Inhibition of myostatin in mice improves insulin sensitivity via irisin-mediated cross talk between muscle and adipose tissues
Open accessAbstract
Background/objective In mice, a high-fat diet (HFD) induces obesity, insulin resistance and myostatin production. We tested whether inhibition of myostatin in mice can reverse these HFD-induced abnormalities.Subjects/methods C57BL/6 mice were fed a HFD for 16 weeks including the final 4 weeks some mice were treated with an anti-myostatin peptibody. Body composition, the respiratory exchange ratio plus glucose and insulin tolerance tests were examined. Myostatin knock down in C2C12 cells was performed using small hairpin RNA lentivirus. Adipose tissue-derived stem cells were cultured to measure their responses to conditioned media from C2C12 cells lacking myostatin, or to recombinant myostatin or irisin. Isolated peritoneal macrophages were treated with myostatin or irisin to determine whether myostatin or irisin induce inflammatory mechanisms.Results In HFD-fed mice, peptibody treatment stimulated muscle growth and improved insulin resistance. The improved glucose and insulin tolerances were confirmed when we found increased muscle expression of p-Akt and the glucose transporter, Glut4. In HFD-fed mice, the peptibody suppressed macrophage infiltration and the expression of proinflammatory cytokines in both the muscle and adipocytes. Inhibition of myostatin caused the conversion of white (WAT) to brown adipose tissue, whereas stimulating fatty acid oxidation and increasing energy expenditure. The related mechanism is a muscle-to-fat cross talk mediated by irisin. Myostatin inhibition increased peroxisome proliferator-activated receptor gamma, coactivator 1α expression and irisin production in the muscle. Irisin then stimulated WAT browning. Irisin also suppresses inflammation and stimulates macrophage polarization from M1 to M2 types.Conclusions These results uncover a metabolic pathway from an increase in myostatin that suppresses irisin leading to the activation of inflammatory cytokines and insulin resistance. Thus, myostatin is a potential therapeutic target to treat insulin resistance of type II diabetes as well as the shortage of brown/beige fat in obesity.
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“In vitro trials demonstrate that myostatin inhibitors increase muscle mass and strength446, suppress irisin, downregulate inflammatory cytokines and improve insulin resistance447.”
From Sarcopenic obesity in older adults: aetiology, epidemiology and treatment strategies (2018) · cites this paper as [447]
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“It contributes to the induction of PGC-1α, FNDC5, and irisin in SkM [27,49,133].”
From The Role of Exercise in the Interplay between Myokines, Hepatokines, Osteokines, Adipokines, and Modulation of Inflammation for Energy Substrate Redistribution and Fat Mass Loss: A Review (2020) · cites this paper as [49]
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“The possibility of an inter-myokine axis with irisin [44,49] and crosstalk with follistatin could represent a mechanism through which myostatin is decreased by exercise.”
From The Role of Exercise in the Interplay between Myokines, Hepatokines, Osteokines, Adipokines, and Modulation of Inflammation for Energy Substrate Redistribution and Fat Mass Loss: A Review (2020) · cites this paper as [49]
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“As also shown in Figure 2 (to facilitate sequence flow, the steps appear numbered as they are introduced in the main text in italics), in the short term, irisin might directly favor a shift from M1 Mφ to a M2 phenotype [49,59], as well as decrease the expression of TLR4, TNF-α, IL-1β, MCP-1, and IL-6 by adipocytes and Mφ [51,53,59] (1a), while increasing IL-10 [59] (1b) and antioxidant cellular me”
From The Role of Exercise in the Interplay between Myokines, Hepatokines, Osteokines, Adipokines, and Modulation of Inflammation for Energy Substrate Redistribution and Fat Mass Loss: A Review (2020) · cites this paper as [49]
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Citations
Cites
Inflammation and metabolic disorders
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Beige Adipocytes Are a Distinct Type of Thermogenic Fat Cell in Mouse and Human
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Double muscling in cattle due to mutations in the myostatin gene
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Sarcopenic obesity in older adults: aetiology, epidemiology and treatment strategies
Batsis, J. A., & Villareal, D. T. (2018) · Nature Reviews Endocrinology · doi:10.1038/s41574-018-0062-9 · Cited by 1,382
Kalinkovich, A., & Livshits, G. (2017) · Ageing Research Reviews · doi:10.1016/j.arr.2016.09.008 · Cited by 882
Physiology and role of irisin in glucose homeostasis
Perakakis, N., Triantafyllou, G. A., Fernández-Real, J. M., Huh, J. Y., Park, K. H., Seufert, J., & Mantzoros, C. S. (2017) · Nature Reviews Endocrinology · doi:10.1038/nrendo.2016.221 · Cited by 621
Emerging Targets in Type 2 Diabetes and Diabetic Complications
Demir, S., Nawroth, P. P., Herzig, S., & Üstünel, B. E. (2021) · Advanced Science · doi:10.1002/advs.202100275 · Cited by 582
PGC-1α as a Pivotal Factor in Lipid and Metabolic Regulation
Cheng, C., Ku, H., & Lin, H. (2018) · International Journal of Molecular Sciences · doi:10.3390/ijms19113447 · Cited by 450
Metadata
- Authors
- Dong, J., Dong, Y., Dong, Y., Chen, F., Mitch, W. E., & Zhang, L.
- Affiliations
- Baylor College of Medicine (US)
- Sichuan University (CN)
- Corresponding author
- Chen, F
- Zhang, L
- Venue
- International Journal of Obesity
- Published
- 2015-10-05
- Volume
- 40
- Issue
- 3
- Pages
- 434-442
- ISSN
- 0307-0565 (ISSN-L)
- 1476-5497
- PMC
- PMC4783239
- OpenAlex
- W2235165689
- Cited by
- 212
- References
- 60
- Citations by year
- 2026: 11 · 2025: 19 · 2024: 18 · 2023: 22 · 2022: 28 · 2021: 32 · 2020: 16 · 2019: 21 · 2018: 14 · 2017: 21 · 2016: 10
- FWCI
- 11.76
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- International Journal of Obesity (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute of Diabetes and Digestive and Kidney Diseases (R37-DK-37175, R37DK037175, P30DK079638, R01DK037175)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adipokines, Inflammation, and Metabolic Diseases
- Health Sciences › Medicine › Physiology (medical) › Adipose Tissue and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Muscle Physiology and Disorders
- Keywords
- myostatin inhibition, irisin, insulin resistance, high-fat diet, brown adipose tissue browning, white adipose tissue, macrophage polarization, inflammation, PPARγ, PGC-1α, type 2 diabetes, obesity, fatty acid oxidation, energy expenditure
- MeSH terms
- Adipose Tissue, Animals, Disease Models, Animal, Insulin, Insulin Resistance, Male, Mice, Inbred C57BL, Muscle, Skeletal, Receptor Cross-Talk, Lipid Metabolism, Proto-Oncogene Proteins c-akt, Mice, Myostatin, Molecular Targeted Therapy, Diet, High-Fat
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