Long-term therapy with Bendavia (MTP-131), a novel mitochondria-targeting peptide, normalizes skeletal muscle fiber type composition in dogs with chronic heart failure

Abstract

Background: Chronic heart failure (HF) is associated with a shift in skeletal muscle (SM) fiber type composition manifested by a decline in the number of aerobic, slow-twitch, fatigue-resistant type-1 fibers and an increase in the number of glycolytic, fast-twitch type-2 fibers. This fiber type shift is responsible, in part, for exercise intolerance in HF. Bendavia (MTP-131), a novel, first in class, MITO-targeting peptide, improves LV systolic function in dogs with chronic HF and restores ATP synthesis in multiple organs including heart, kidney and SM in other animal models of disease. We tested the hypothesis that long-term therapy with Bendavia can reverse the maladaptive SM fiber type shift in dogs with chronic HF possibly through restored MITO oxidative capacity. Methods: Studies were performed in triceps SM samples of 14 HF dogs produced by intracoronary microembolizations (LV ejection fraction ∼30%) and from 9 normal dogs. HF dogs were randomized to 3 months therapy with subcutaneous injections of Bendavia (0.5 mg/kg once daily, n=7) or saline (Control, n=7). SM type-1 and -2 fibers were differentiated histologically by myofibrillar adenosine triphosphatase staining. The proportion of Type-1 and -2 fibers and the average cross-sectional area (CSA) of each fiber type was assessed in 5 randomly selected SM fields/dog each containing ∼100 fibers. Results: The proportion of SM type-1 fibers was lower and type-2 fibers higher in HF-Control compared to normal (table) leading to a significantly lower fiber type ratio. Treatment with Bendavia restored a near normal fiber type composition. There were no differences in SM CSA among study groups (table). Skeletal Muscle Fiber Type Composition *p<0.05 vs. Normal; †p<0.05 vs. HF-Control. Conclusions: Therapy with Bendavia reverses abnormalities of SM fiber type without influencing SM CSA. Reversal of this SM maladaptation following therapy with Bendavia can lead to improved exercise tolerance in HF.