Mature-onset obesity in p62-deficient male mice maintains skeletal muscle mass despite metabolic dysfunction

Sequestosome 1 (p62/SQSTM1) is a multifunctional scaffolding protein at the intersection of autophagy and metabolic regulation. While p62 deficiency causes mature-onset obesity and insulin resistance, its effects on skeletal muscle mass and function remain poorly understood. Male p62 knockout (p62^-/^-) and wildtype control mice (n = 9/group) were studied from 14 to 34 weeks of age. p62^-/^- mice exhibited greater food intake (+19.1%, p = 0.016), progressive weight gain (+41.5%, p < 0.001), and markedly elevated fat mass (+72.2%, p = 0.001), while lean mass was unchanged. Fasting hyperglycemia and impaired glucose tolerance (p < 0.05) confirmed systemic metabolic dysfunction. Despite this, p62^-/^- mice maintained grip strength, skeletal muscle weights, and myofiber cross-sectional areas comparable to controls. Molecular analysis revealed significantly elevated NBR1 (+61.6%, p = 0.020) and phospho-mTOR (+78.2%, p = 0.033) in soleus muscle, suggesting altered autophagic flux. p62-deficient male mice developed severe obesity and insulin resistance while maintaining skeletal muscle mass and grip strength at this intermediate timepoint. This phenotype was associated with altered mTOR and autophagy signaling. Whether muscle preservation is sustained long-term warrants further investigation, as chronic obesity and metabolic dysfunction may ultimately impair muscle health.