Elamipretide improves skeletal muscle function in heart failure with preserved ejection fraction rats: a mitochondrial, physiological and molecular analysis

Aim Exercise intolerance, promoted by skeletal muscle (SKM) and mitochondrial dysfunction, is a common hallmark of patients who suffer from heart failure with preserved ejection fraction (HFpEF). In the context of mitochondrial dysfunction, studies showed impaired cardiolipin function in the myocardium of HFpEF animals and patients, but changes in the SKM were never investigated. Elamipretide (Ela) represents a potential therapeutic strategy targeting disturbed cardiolipin function. This approach has been investigated in several studies on heart failure with reduced ejection fraction (HFrEF), yielding controversial results. Aim of the present study was to investigate cardiolipin dysregulation in the SKM of HFpEF rats and to analyze the effect of Ela treatment, which is proposed to stabilize cardiolipin (CL). Methods ZSF-1 lean (n=10, con) and obese rats (n=24, HFpEF) were used in this study. At 20-weeks of age HFpEF rats were randomized into two groups receiving NaCl (n=12, placebo) or Ela (n=12, treated) via osmotic minipumps. After 12 weeks of treatment in vitro SKM force and mitochondrial function were assessed. SKM (Soleus (Sol) + Extensor digitorum longus (EDL)) tissue was collected for single-fiber mechanics, histological, and molecular analyses. Results A slow-to-fast fiber type shift was evident (Sol: - 8.4 % change, p = 0.006, EDL: - 0.8 % change, p = 0.05), that could be prevented by Ela treatment (Sol: + 10.5 % change, p = 0.0001, EDL: + 1.1 % change, p = 0.005). Ela treatment was also able to prevent muscle atrophy (Sol: + 49.1 %, p = 0.01, EDL: + 54.8 %, p = 0.003), reduced force on whole muscle- (Sol: + 6.2 %, p = 0.04, EDL: + 9.2 %, p = 0.04), as well as on single fiber level (Sol: + 173.2 %, p < 0.0001) (Figure 1), titin S11878 hyperphosphorylation (Sol: - 29.8 %, p = 0.004, EDL: - 32.0 %, p = 0.0004) and decreased mitochondrial complex II activity (Sol SDH-activity: + 23.2 %, p = 0.003). HFpEF-rats showed decreased CL-levels (Sol: - 6.8 %, p = 0.007, EDL: - 14.2 %, p = 0.02) and tafazzin expression (Sol: - 65.2 %, p = 0.03, EDL: - 36.5 %, p = 0.02). Furthermore, significant correlations between mitochondrial function, force and CL content could be detected (Figure 2). Conclusions This study highlights a strong link between SKM force, mitochondrial function, as well as CL content and maturation in HFpEF. In the EDL impaired thin- and thick-filament interactions and disrupted sarcomere structure, was observed, while the Sol remained largely unaffected. In the present study, Ela treatment exerted pronounced effects on mitochondrial function in SKM, likely through cardiolipin-mediated improvements in oxidative phosphorylation. In SKM, Ela induced multiple beneficial effects, likely contributing to the restoration of physiological muscle stiffness. These findings highlight Ela as a promising therapeutic strategy for SKM dysfunction in HFpEF.