GNMT alleviates heart failure-induced skeletal muscle atrophy by regulating ATP5J2-mediated mitochondrial metabolic reprogramming through succinylation.

Heart failure (HF) is defined as a condition characterized by abnormalities in the heart's structure or function, which lead to the heart's inability to deliver oxygen to tissues in a timely manner, and it may progress to symptoms such as muscle atrophy of skeletal muscles. Our research primarily focuses on Glycine N-methyltransferase (GNMT), an enzyme that utilizes S-adenosylmethionine (SAM) to catalyze glycine, in order to explore its specific role in HF-induced skeletal muscle atrophy. In this study, an HF rat model induced by abdominal aortic constriction (AAC) and a C2C12 muscle atrophy cell model induced by angiotensin Ⅱ (Ang Ⅱ) were established. Echocardiography, ELISA, and HE staining were used to evaluate the damage of myocardial and gastrocnemius tissues. Immunofluorescence staining was used to assess skeletal muscle atrophy. Western blot, IP, and Co-IP were used to determine the molecular mechanism. In HF rats, the expressions of GNMT and Mitochondrial Fo complex subunit F2 (ATP5J2) were significantly decreased. Overexpression of GNMT/ATP5J2 contributed to alleviate HF-induced skeletal muscle atrophy. GNMT elevated the succinylation level and protein stability of ATP5J2 at lysine 22 (K22) by consuming glycine, and simultaneously reduced its ubiquitination level. Succinylated ATP5J2 improved mitochondrial homeostasis to mitigate HF-induced skeletal muscle atrophy. This study elucidated the function of the GNMT-ATP5J2 axis in HF-induced skeletal muscle atrophy and clarified the underlying molecular mechanism, providing a new theoretical basis for the treatment of HF-induced skeletal muscle atrophy.