Voluntary wheel running attenuates peptidoglycan–polysaccharide‐induced inflammation and preserves skeletal muscle remodeling in male C57BL / 6J mice

Chronic systemic inflammation (CSI) is associated with skeletal muscle dysfunction and may impair adaptive responses. This study investigated whether skeletal muscle responses to voluntary wheel running (VWR) are maintained following exposure to CSI. Twelve-week-old male C57BL/6J mice were assigned to Saline+Sedentary, Peptidoglycan-Polysaccharide (PG-PS) + Sedentary, Saline+Exercise, and PG-PS + Exercise groups (n = 12 per group), with PG-PS used to induce CSI. Following 3 weeks of intervention, blood and lower-leg skeletal muscles were collected. Total running distance did not differ between exercise groups. PG-PS administration increased serum tumor necrosis factor-α and interleukin-1β levels in sedentary mice, whereas these levels were attenuated in VWR mice. Under sedentary conditions, soleus muscle weight and fiber cross-sectional area (CSA) were lower in PG-PS-treated mice. Exercise was associated with higher soleus muscle mass and fiber CSA in both saline- and PG-PS-treated mice. PG-PS increased 4-hydroxynonenal levels in the soleus muscle, whereas VWR was associated with lower levels. VWR markedly increased muscle protein synthesis and reduced markers of muscle protein breakdown, indicating enhanced protein turnover independent of PG-PS treatment. These findings suggest that exercise-induced increases in muscle mass and fiber size occur independent of PG-PS treatment. Clinically, whole-body exercise may represent a physiologically relevant, non-pharmacological strategy to support skeletal muscle health under chronic inflammatory conditions.