Overexpression of heart-specific small subunit of myosin light chain phosphatase results in heart failure and conduction disturbance.

Abstract

Mutations in genes encoding components of the sarcomere cause cardiomyopathy, which is often associated with abnormal Ca2+ sensitivity of muscle contraction. We have previously shown that a heart-specific myosin light chain phosphatase small subunit (hHS-M21) increases the Ca2+ sensitivity of muscle contraction. The aim of the present study was to investigate the function of hHS-M21 in vivo and the causative role of abnormal Ca2+ sensitivity in cardiomyopathy. We generated transgenic mice with cardiac-specific overexpression of hHS-M21. We confirmed that hHS-M21 increased the Ca2+ sensitivity of cardiac muscle contraction in vivo, which was not followed by an increased phosphorylation of myosin light chain 2 isoforms. hHS-M21 transgenic mice developed severe systolic dysfunction with myocardial fibrosis and degeneration of cardiomyocytes in association with sinus bradycardia and atrioventricular conduction defect. The contractile dysfunction and cardiac fibrosis were improved by treatment with the Rho kinase inhibitor fasudil. Our findings suggested that the overexpression of hHS-M21 results in cardiac dysfunction and conduction disturbance via non-myosin light chain 2 phosphorylation-dependent regulation. NEW & NOTEWORTHY The present study is the first to develop mice with transgenic overexpression of a heart-specific myosin light chain phosphatase small subunit (hHS-M21) and to examine the effects of hHS-M21 on cardiac function. Elevation of hHS-M21 induced heart failure with myocardial fibrosis and degeneration of cardiomyocytes accompanied by supraventricular arrhythmias.

• Authors: Takuro Arimura, Antoine Muchir, Masayoshi Kuwahara, Sachio Morimoto, Taisuke Ishikawa, Cheng-Kun Du, Dong-Yun Zhan, Shu Nakao, Noboru Machida, Ryo Tanaka, Yoshihisa Yamane, Takeharu Hayashi, Akinori Kimura
• Journal: American journal of physiology. Heart and circulatory physiology (Am J Physiol Heart Circ Physiol) Vol. 314 Issue 6 Pg. H1192-H1202 (06 01 2018) ISSN: 1522-1539 [Electronic] United States
• PMID: 29451818 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Myosin Light Chains
• Protein Subunits
• myosin light chain 2
• rho-Associated Kinases
• Myosin-Light-Chain Phosphatase
• Cardiac Myosins

Topics

• Animals
• Arrhythmias, Cardiac (enzymology, genetics, pathology, physiopathology)
• Calcium Signaling
• Cardiac Myosins (metabolism)
• Cardiomyopathies (enzymology, genetics, physiopathology)
• Disease Models, Animal
• Fibrosis
• Genetic Predisposition to Disease
• Heart Failure (enzymology, genetics, pathology, physiopathology)
• Heart Rate
• Humans
• Mice, Inbred C57BL
• Mice, Transgenic
• Myocardial Contraction
• Myocytes, Cardiac (enzymology, pathology)
• Myosin Light Chains (metabolism)
• Myosin-Light-Chain Phosphatase (genetics, metabolism)
• Phenotype
• Phosphorylation
• Protein Subunits
• Up-Regulation
• Ventricular Dysfunction, Left (enzymology, genetics, physiopathology)
• Ventricular Function, Left
• Ventricular Remodeling
• rho-Associated Kinases (metabolism)