Ghrelin attenuates skeletal-muscle atrophy by regulating muscle protein degradation and lung inflammation in aged male mice with lipopolysaccharide-induced lung injury

Sarcopenia is a progressive and generalized skeletal muscle disorder characterized by reduced muscle mass and strength, leading to adverse outcomes such as frailty and increased mortality. Pneumonia can accelerate the progression of sarcopenia, particularly in older adults, by promoting systemic inflammation, reducing physical activity, and impairing respiratory and swallowing muscle function. No effective therapeutic interventions for sarcopenia have been established. Ghrelin, an endogenous ligand for the growth hormone secretagogue receptor (GHSR), is produced primarily in the stomach and is known to stimulate appetite, suppress inflammation, and prevent muscle catabolism. Here, we showed that intraperitoneal ghrelin given every 12 h attenuated skeletal-muscle atrophy in aged mice with lipopolysaccharide (LPS)-induced lung injury. Ghrelin treatment preserved muscle weight and mass, suppressed the FoxO1-dependent expression of muscle-specific E3 ubiquitin ligases, muscle RING-finger protein-1, and F-Box protein 32 in the gastrocnemius muscle, and improved the muscle contractile force and voluntary wheel-running activity. In parallel, ghrelin treatment attenuated histological lung injury and was associated with lower levels of inflammatory cytokines in bronchoalveolar lavage fluid. In vitro, ghrelin treatment of LPS-stimulated C2C12 myotubes suppressed reactive oxygen species accumulation and increased the expression of redox-regulating genes including peroxisome proliferator-activated receptor gamma coactivator 1-α and superoxide dismutase 2. Ghrelin also downregulated the LPS-induced expression of muscle-specific ubiquitin ligases in C2C12 cells. These findings suggest that ghrelin has a protective role against inflammation-associated skeletal-muscle atrophy and may have potential as a therapeutic agent for respiratory sarcopenia in the elderly.