| First Author | Yang KC | Year | 2019 |
| Journal | J Mol Cell Cardiol | Volume | 137 |
| Pages | 9-24 | PubMed ID | 31629737 |
| Mgi Jnum | J:294355 | Mgi Id | MGI:6451268 |
| Doi | 10.1016/j.yjmcc.2019.09.009 | Citation | Yang KC, et al. (2019) Deficiency of nuclear receptor interaction protein leads to cardiomyopathy by disrupting sarcomere structure and mitochondrial respiration. J Mol Cell Cardiol 137:9-24 |
| abstractText | BACKGROUND: Cardiomyopathy is a common and lethal complication in patients with limb-girdle muscular dystrophy (LGMD), one of the most prevalent forms of muscular dystrophy. The pathogenesis underlying LGMD-related cardiomyopathy remains unclear. NRIP (gene name DCAF6), a Ca(2+)-dependent calmodulin binding protein, was reduced in dystrophic muscles from LGMD patients. Mice lacking NRIP exhibit a myopathic phenotype resembling that in LGMD patients, making NRIP deficiency a potential culprit leading to cardiomyopathy. This study aimed to determine if NRIP deficiency leads to cardiomyopathy and to explore the underlying molecular mechanisms. METHODS AND RESULTS: NRIP expression was reduced in both human and mouse failing hearts. Muscle-specific NRIP knockout (MCK-Cre::Dcaf6(flox/flox)) mouse heart and isolated cardiomyocytes exhibited markedly reduced contractility. Transmission electron microscopy revealed abnormal sarcomere structures and mitochondrial morphology in MCK-Cre::Dcaf6(flox/flox) hearts. Protein co-immunoprecipitation and confocal imaging revealed that NRIP interacts with alpha-actinin 2 (ACTN2) at the Z-disc. We found that NRIP facilitated ACTN2-mediated F-actin bundling, and that NRIP deficiency resulted in reduced binding between Z-disc proteins ACTN2 and Cap-Z. In addition, NRIP-deficiency led to increased mitochondrial ROS and impaired mitochondrial respiration/ATP production owing to elevated cellular NADH/NAD(+) ratios. Treatment with mitochondria-directed antioxidant mitoTEMPO or NAD(+) precursor nicotinic acid restored mitochondrial function and cardiac contractility in MCK-Cre::Dcaf6(flox/flox) mice. CONCLUSIONS: NRIP is essential to maintain sarcomere structure and mitochondrial/contractile function in cardiomyocytes. Our results revealed a novel role for NRIP deficiency in the pathogenesis of LGMD and heart failure. Targeting NRIP, therefore, could be a powerful new approach to treat myocardial dysfunction in LGMD and heart failure patients. |
