Skeletal muscle dysfunction in aged mice with heart failure with preserved ejection fraction is associated with impaired mitochondrial bioenergetics

Skeletal muscle dysfunction contributes significantly to exercise intolerance and reduced quality of life in patients with heart failure with preserved ejection fraction (HFpEF), particularly in older individuals. Recent clinical data indicate that these impairments are strongly associated with mitochondrial abnormalities. However, current mouse models of HFpEF do not fully recapitulate the muscle phenotype observed in humans. We recently demonstrated that aging exacerbates the cardiometabolic HFpEF phenotype in mice and is accompanied by loss of muscle mass. Thus, we hypothesized that aging induces skeletal muscle and mitochondrial dysfunction in a murine model of cardiometabolic HFpEF, resulting in a phenotype more consistent with human disease. To test this, we induced HFpEF in 19-month-old male mice using a 15-week two-hit protocol combining high-fat diet and L-NAME. Skeletal muscle health was assessed by grip strength, treadmill exhaustion tests, quantitative magnetic resonance (QMR), metabolic cage studies with indirect calorimetry and muscle wet weight analysis. Mitochondrial function was evaluated by high-resolution respirometry with ADP titration in permeabilized gastrocnemius muscle fibers. Aged mice developed the expected HFpEF phenotype, including concentric hypertrophy, diastolic dysfunction and pulmonary congestion. QMR analysis revealed increased fat mass and elevated total body water despite lower water consumption, consistent with fluid retention. Muscle weakness developed early, with significant impairments in grip strength after 5 weeks that persisted through 15 weeks. HFpEF mice showed pronounced exercise intolerance, demonstrated by reduced treadmill running capacity. Metabolic cage assessments showed no change in spontaneous activity, indicating that functional decline was not driven by inactivity. Aged HFpEF mice had skeletal muscle atrophy, with lower mass in tibialis anterior, gastrocnemius, plantaris, and extensor digitorum longus muscles compared to age-matched controls, while soleus mass remained unchanged. Indirect calorimetry showed a lower respiratory exchange ratio in HFpEF mice compared to controls, suggesting a shift toward greater reliance on fatty acid oxidation. Muscle from HFpEF mice showed slower rates of complex I- and complex II-supported mitochondrial respiration, along with a diminished maximal oxidative phosphorylation capacity compared with controls. Moreover, they had a lower oxidative phosphorylation-to-electron transport capacity ratio, indicating impaired efficiency of the oxidative phosphorylation system. These findings demonstrate that aged mice with cardiometabolic HFpEF develop robust skeletal muscle dysfunction accompanied by significantly impaired mitochondrial bioenergetics. This work recapitulates the skeletal muscle phenotype characteristic of human HFpEF and provides a clinically relevant model for investigating skeletal muscle abnormalities and developing targeted strategies to improve mitochondrial dysfunction. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.