Aerobic exercise partially improves the skeletal muscle phenotype in a model of heart failure with preserved ejection fraction in male mice.

Heart failure with preserved ejection fraction (HFpEF) is associated with skeletal muscle dysfunction that contributes to exercise intolerance and disease progression. Altered Ca2+ homeostasis and increased oxidative stress have been proposed as mechanisms underlying muscle weakness in HFpEF; however, the effects of aerobic exercise on skeletal muscle physiology in this condition remain unclear. This study evaluated the impact of moderate-intensity aerobic exercise on skeletal muscle contractile function, fatigue resistance, oxidative stress, and mRNA expression of key Ca2+-handling proteins in a model with features consistent with HFpEF. Male C57BL/6J mice were assigned to Control, Exercise, HFpEF (HFD + L-NAME-treated), and HFpEF+Exercise groups. HFpEF-like features were induced by an 8-week high-fat diet combined with L-NAME administration. During the final 4 weeks, mice underwent aerobic exercise training. Soleus muscles were analyzed using in vitro contractile recordings, oxidative stress markers, and RT-qPCR for RyR1, SERCA1, and NCX3 mRNA expression. HFpEF (HFD + L-NAME-treated mice) showed reduced contractile force and fatigue resistance, increased oxidative stress, and decreased SERCA1 and NCX3 expression. Aerobic exercise partially restored muscle performance and improved redox balance without normalizing Ca2+-handling gene expression. These findings suggest that aerobic exercise enhances skeletal muscle function in HFpEF-like models, primarily by modulating redox homeostasis.