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Aims  Elamipretide (ELAM), an aromatic–cationic tetrapeptide, interacts with cardiolipin and normalizes dysfunctional mitochondria of cardiomyocytes. This study examined the effects of ELAM on skeletal muscle mitochondria function in dogs with chronic heart failure (HF).    Methods and results  Studies were performed in skeletal muscle biopsy specimens obtained from normal dogs ( n  = 7) and dogs with chronic intracoronary microembolization‐induced HF ( n  = 14) treated with subcutaneous ELAM 0.5 mg/kg (HF + ELAM,  n  = 7) or vehicle (normal saline control, HF‐CON,  n  = 7). After 3 months of therapy, triceps skeletal muscle samples were obtained from all dogs, and the proportion of type 1 and type 2 fibres was assessed. Mitochondria isolated from myofibrils of the vastus lateralis skeletal muscle exposed  in vitro  to ELAM for 1 h were used to assess mitochondrial function. The proportion of skeletal muscle type 1 fibres was lower in HF‐CON dogs compared with normal dogs (23 ± 4 vs. 32 ± 5%,  P  < 0.05). Treatment with ELAM restored a near‐normal fibre‐type composition (31 ± 7%,  P  < 0.05 vs. HF‐CON). Skeletal muscle mitochondria showed significantly lower levels of adenosine diphosphate‐dependent mitochondrial respiration (100 ± 9 vs. 164 ± 15 natom O/min/mg protein,  P  < 0.05), mitochondrial membrane potential (0.17 ± 0.03 vs. 0.53 ± 0.03 red/green fluorescence ratio,  P  < 0.05), mitochondrial permeability transition pore (38 ± 3 vs. 62 ± 2 relative light units,  P  < 0.05), maximum rate of adenosine triphosphate synthesis (3284 ± 418 vs. 8835 ± 423 RLU/μg protein,  P  < 0.05), and cytochrome  c  oxidase activity (1390 ± 108 vs. 2459 ± 210 natom O/min/mg protein,  P  < 0.05) compared with normal dogs. Exposure of skeletal muscle myofibrillar mitochondria from HF dogs to ELAM showed a dose‐dependent improvement/normalization of all measures of mitochondrial function. In mitochondria from skeletal muscle of HF dogs exposed to 0.10 μM ELAM, adenosine diphosphate‐dependent mitochondrial respiration increased to 183 ± 18 natom O/min/mg protein, membrane potential increased to 0.30 ± 0.03 red/green fluorescence ratio, mitochondrial permeability transition pore increased to 54 ± 4 RLU, maximum rate of adenosine triphosphate synthesis increased to 4423 ± 414, and cytochrome  c  oxidase activity increased to 2033 ± 191 natom O/min/mg protein. Exposure of skeletal muscle myofibrillar mitochondria from normal dogs to ELAM had no effect on mitochondrial function parameters.    Conclusions  The results indicate that ELAM, previously shown to positively influence mitochondrial function of the failing heart, can also positively impact mitochondrial function of skeletal muscle and potentially help restore skeletal muscle function and improve exercise tolerance.

Effects of elamipretide on skeletal muscle in dogs with experimentally induced heart failure