Glucagon receptor deficiency is associated with glucocorticoid receptor activation and proteolytic remodeling in gastrocnemius of male mice.

Glucagon receptor (GCGR) signaling plays a central role in systemic metabolic regulation. However, its role in skeletal muscle protein homeostasis remains poorly understood. In this study, we demonstrated that skeletal muscle from male GCGR-deficient mice exhibited preferential gastrocnemius atrophy accompanied by elevated intramuscular free amino acid levels and hyperaminoacidemia. Transcriptomic and biochemical analyses revealed activation of glucocorticoid receptor (GR) signaling together with induction of proteolytic pathways, as reflected by increased TRIM63 and FBXO32 levels, elevated LC3B-II/I ratio, and reduced p62 levels. Notably, GCGR deficiency was associated with increased corticosterone and subsequent GR activation. In cultured myotubes, serum from male Gcgr-/- mice induced GR activation, enhanced proteolysis, and increased intracellular free amino acid levels, all of which were attenuated by GR antagonism. Consistently, dexamethasone stimulation increased net amino acid accumulation in the culture medium. Moreover, the GR activation-resulted gastrocnemius atrophy was alleviated by GLP-1R antagonism. These findings link GCGR deficiency to GR activation, gastrocnemius proteolysis, hyperaminoacidemia and elevated GLP-1 signaling, suggesting a role for skeletal muscle in systemic amino acid homeostasis under impaired GCGR signaling.