Targeting Mitochondrial Dysfunction With Elamipretide (SS-31) Improves Skeletal Muscle Performance in a HFpEF Rat Model

BACKGROUND: Exercise intolerance, promoted by skeletal muscle- and mitochondrial dysfunction, has been identified as a therapeutic target in heart failure with preserved ejection fraction (HFpEF). In the context of mitochondrial dysfunction, altered cardiolipin integrity has been reported in the myocardium of HFpEF, suggesting Elamipretide, a cardiolipin stabilizing agent, as potential therapeutic approach. The present study investigated cardiolipin dysregulation in the skeletal muscle of HFpEF rats and analyzed the effect of Elamipretide treatment. METHODS: Female zucker fatty spontaneously hypertensive heart failure F1 hybrid lean (n=10, control) and obese rats (n=24, HFpEF) were included. At 20 weeks of age, HFpEF rats were randomized into 2 groups receiving NaCl (n=12) or Elamipretide (n=12) for 12 weeks. Skeletal muscle tissue was collected for whole-muscle force, single-fiber mechanics, mitochondrial respiration, histology and molecular analyses. RESULTS: HFpEF rats exhibited reduced cardiolipin levels (−6.8%, P =0.007) and maturation (shown via tafazzin expression), contractile dysfunction, titin hyperphosphorylation, fiber atrophy and increased oxidative stress markers. Elamipretide improved whole muscle (soleus: +8.2%, P =0.041, extensor digitorum longus: +10.9%, P =0.016) and single-fiber (soleus: +173.2%, P <0.001, extensor digitorum longus: +66.0%, P =ns) contractile function and titin phosphorylation (soleus: −35.4%, P <0.001, extensor digitorum longus: −40.2%, P <0.001), while preventing atrophy development (soleus: +49%, P =0.001, extensor digitorum longus: +54.8%, P <0.001). Improved mitochondrial function, presumably through cardiolipin-mediated improvements in oxidative phosphorylation, could be associated with muscle force and cardiolipin integrity. CONCLUSIONS: Our data highlight cardiolipin stabilization as a key modulator of mitochondrial and contractile function in HFpEF, identifying Elamipretide as a promising therapeutic approach for skeletal muscle dysfunction.