Skeletal muscle mitochondrial complex I dysfunction in cardiac hypertrophy and failure

Abstract

Skeletal muscle function plays an important role in exercise intolerance associated with heart failure (HF). We have previously shown a reduced maximum respiratory rate (JO2max) and complex I dysfunction in skeletal muscle mitochondria from rats with HF, consistent with a bioenergetic limitation to exercise. This study aimed to determine whether complex I dysfunction was also manifest in compensated ventricular hypertrophy (CH). Monocrotaline treatment was used to induce right ventricular HF (60 mg.kg−1; n = 9) and CH (30 mg.kg−1; n = 6) compared to saline (CON; n = 9). After 23 ± 1 (mean, SE) days decompensated HF was verified by weight loss and clinical symptoms. Mitochondrial function of saponin-permeabilized fibers from the plantaris muscle was assessed in a high-resolution respirometer (Oroboros). Uncoupled JO2max (pyruvate, malate, glutamate, succinate, ADP and FCCP) was significantly (P<0.05) lower in HF (47.6 ± 3.3 pmol O2.s−1.mg−1) than CH (56.7 ± 6.5) or CON (53.0 ± 3.3). Blocking complex I with rotenone reduced the respiratory rate to a greater (P<0.05) degree in CON (37 ± 2 %) than in HF (29 ± 3 %) or CH (28 ± 3 %). Thus complex I dysfunction in CH precedes the reduction in skeletal muscle mitochondrial content seen in HF. A reduced ADP-sensitivity of respiration due to complex I dysfunction, therefore, may contribute to a bioenergetic limitation in CH, which is later exacerbated by mitochondrial loss in HF.