Kcnma1 is involved in mitochondrial homeostasis in diabetes‐related skeletal muscle atrophy

Abstract Uncontrolled diabetes causes a catabolic state with multi‐organic complications, of which impairment on skeletal muscle contributes to the damaged mobility. Kcnma1 gene encodes the pore‐forming α‐subunit of Ca 2+ ‐ and voltage‐gated K + channels of large conductance (BK channels), and loss‐of‐function mutations in Kcnma1 are in regards to impaired myogenesis. Herein, we observed a time‐course reduction of Kcnma1 expression in the tibialis anterior muscles of leptin receptor‐deficient (db/db) diabetic mice. To investigate the role of Kcnma1 in diabetic muscle atrophy, muscle‐specific knockdown of Kcnma1 was achieved by mice receiving intravenous injection of adeno‐associated virus‐9 (AAV9)‐encoding shRNA against Kcnma1 under the muscle creatine kinase (MCK) promoter. Impairment on muscle mass and myogenesis were observed in m/m mice with AAV9‐sh Kcnma1 intervention, while this impairment was more obvious in diabetic db/db mice. Simultaneously, damaged mitochondrial dynamics and biogenesis showed much severer in db/db mice with AAV9‐sh Kcnma1 intervention. RNA sequencing revealed the large transcriptomic changes resulted by Kcnma1 knockdown, and changes in mitochondrial homeostasis‐related genes were validated. Besides, the artificial alteration of Kcnma1 in mouse C2C12 myoblasts was achieved with an adenovirus vector. Consistent results were demonstrated by Kcnma1 knockdown in palmitate‐treated cells, whereas opposite results were exhibited by Kcnma1 overexpression. Collectively, we document Kcnma1 as a potential keeper of mitochondrial homeostasis, and the loss of Kcnma1 is a critical event in priming skeletal muscle loss in diabetes.