FNDC5/Irisin inhibits pathological cardiac hypertrophy.

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.

• Authors: Qing Yu, Wenxin Kou, Xu Xu, Shunping Zhou, Peipei Luan, Xiaopeng Xu, Hailing Li, Jianhui Zhuang, Jun Wang, Yifan Zhao, Yawei Xu, Wenhui Peng
• Journal: Clinical science (London, England : 1979) (Clin Sci (Lond)) Vol. 133 Issue 5 Pg. 611-627 (03 15 2019) ISSN: 1470-8736 [Electronic] England
• PMID: 30782608 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2019 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.

Chemical References

• FNDC5 protein, human
• FNDC5 protein, mouse
• FNDC5 protein, rat
• Fibronectins
• Membrane Proteins
• TOR Serine-Threonine Kinases
• AMP-Activated Protein Kinases
• Amyloid Precursor Protein Secretases
• ADAM10 Protein
• ADAM10 protein, rat
• Adam10 protein, mouse

Topics

• ADAM10 Protein (metabolism)
• AMP-Activated Protein Kinases (metabolism)
• Aged
• Amyloid Precursor Protein Secretases (metabolism)
• Animals
• Cardiomegaly (metabolism, pathology, physiopathology, prevention & control)
• Case-Control Studies
• Cell Line
• Disease Models, Animal
• Female
• Fibronectins (genetics, metabolism)
• Fibrosis
• Humans
• Male
• Membrane Proteins (metabolism)
• Mice
• Middle Aged
• Myocytes, Cardiac (metabolism, pathology)
• Rats, Sprague-Dawley
• Signal Transduction
• TOR Serine-Threonine Kinases (metabolism)
• Ventricular Remodeling