FNDC5/Irisin inhibits pathological cardiac hypertrophy
Abstract
Abstract Cardiac hypertrophy is a common pathophysiological process in various cardiovascular diseases, which still has no effective therapies. Irisin is a novel myokine mainly secreted by skeletal muscle and is believed to be involved in the regulation of energy metabolism. In the present study, we found that irisin expression was elevated in hypertrophic murine hearts and serum. Moreover, angiotension II-induced cardiomyocyte hypertrophy was attenuated after irisin administration and aggravated after irisin knockdown in vitro. Next, we generated transverse aortic constriction (TAC)-induced cardiac hypertrophy murine model and found that cardiac hypertrophy and fibrosis were significantly attenuated with improved cardiac function assessed by echocardiography after irisin treatment. Mechanistically, we demonstrated that FNDC5 was cleaved into irisin, at least partially, in a disintegrin and metalloproteinase (ADAM) family-dependent manner. ADAM10 was the candidate enzyme responsible for the cleavage. Further, we found irisin treatment activated AMPK and subsequently inhibited activation of mTOR. AMPK inhibition ablated the protective role of irisin administration. In conclusion, we find irisin is secreted in an ADAM family-dependent manner, and irisin treatment improves cardiac function and attenuates pressure overload-induced cardiac hypertrophy and fibrosis mainly through regulating AMPK-mTOR signaling.
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Irisin is released primarily from skeletal muscle after physical exercise, and to a lesser extent by white adipose tissue, from its precursor FNDC5, with cleavage probably involving ADAM family proteases.
“Irisin is released primarily from SkM after physical exercise, and to a lesser extent by WAT, from its precursor fibronectin type III domain-containing protein 5 (FNDC5), its cleavage probably involving ADAM family proteases [120].”
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- Authors
- Yu, Q., Kou, W., Xu, X., Zhou, S., Luan, P., Xu, X., Li, H., Zhuang, J., Wang, J., Zhao, Y., Xu, Y., & Peng, W.
- Affiliations
- Tongji University (CN)
- The University of Texas Health Science Center at Houston (US)
- Corresponding author
- Xu, Xu
- Zhao, Yifan
- Xu, Yawei
- Peng, Wenhui
- ORCID
- Venue
- Clinical Science
- Publisher
- Portland Press Ltd.
- Published
- 2019-03-01
- Volume
- 133
- Issue
- 5
- Pages
- 611-627
- ISSN
- 0143-5221 (ISSN-L)
- 1470-8736
- OpenAlex
- W2915355067
- Cited by
- 115
- References
- 28
- Citations by year
- 2026: 11 · 2025: 11 · 2024: 24 · 2023: 17 · 2022: 22 · 2021: 16 · 2020: 13 · 2019: 1
- FWCI
- 9.40
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Clinical Science (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Natural Science Foundation of Shanghai
- National Natural Science Foundation of China
- Topics
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac Fibrosis and Remodeling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Signaling Pathways in Disease
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Muscle Physiology and Disorders
- Keywords
- irisin, FNDC5, cardiac hypertrophy, myocardial fibrosis, angiotensin II, transverse aortic constriction, ADAM10, ADAM family, proteolytic cleavage, AMPK, mTOR signaling, pressure overload, myokines, cardiac function
- MeSH terms
- ADAM10 Protein, Aged, Animals, Cell Line, Disease Models, Animal, Female, Fibronectins, Fibrosis, Cardiomegaly, Humans, Male, Membrane Proteins, Middle Aged, Signal Transduction, Case-Control Studies, Rats, Sprague-Dawley, Ventricular Remodeling, Myocytes, Cardiac, Mice, Amyloid Precursor Protein Secretases, AMP-Activated Protein Kinases, TOR Serine-Threonine Kinases
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