Proceedings of The Physiological Society

University of Manchester (2010) Proc Physiol Soc 19, C62

Oral Communications

Skeletal muscle capillary remodelling and mitochondrial dysfunction occur without a change in fibre type in rats with right heart failure

R. C. Wüst1, D. S. Myers2, J. P. Boyle2, C. Peers2, E. White1, H. B. Rossiter1

1. Institute of Membrane and Systems Biology, University of Leeds, Leeds, United Kingdom. 2. Division of Cardiovascular and Neuronal Remodelling, University of Leeds, Leeds, United Kingdom.


Exercise intolerance is a cardinal symptom of chronic heart failure (HF), and is a better predictor of mortality than central haemodynamics or other established risk factors [1]. Furthermore, correction of the central limitation by heart transplantation does not consistently resolve the functional limitations in HF patients [2], and as such adaptations in skeletal muscle function are thought to play an important role in exercise intolerance in chronic HF. Muscle atrophy, weakness and a higher percentage of more-fatigable fast-twitch fibres have been observed in HF [3,4], and the latter is negatively correlated with peak oxygen uptake [5]. We therefore aimed to determine whether HF-related changes in muscle fibre type precede those of capillarity, mitochondrial density and function. Right ventricle hypertrophy was induced by monocrotaline treatment (60 mg.kg-1; MCT) in 11 rats, compared to saline control (CON; n=11). After 23±1 (mean, SD) days decompensated HF was verified by weight loss and clinical symptoms. Serial sections (10 μm) of the plantaris muscle (deep and superficial region) were stained for ATPase activity (pH=4.50 for fibre type), succinate dehydrogenase (SDH)-activity and capillaries. The mitochondrial function of saponin-permeabilised fibres (8.8±2.4 mg) from the contra-lateral plantaris muscle (n=6 [CON] and 8 [MCT], both regions) was assessed in a high-resolution respirometer (Oroboros, Austria). The plantaris was heavier in CON than MCT: 265±32 vs. 232±18 mg (p=0.001, t-test); and fibre cross-sectional area smaller in MCT: 2322±120 vs. 1843±114 μm2 (p=0.009; ANOVA repeated measures). Overall fibre type distribution in MCT (type I, 9±7; IIa, 15±10; IIa/x, 5±5 and IIx/b, 71±17%) was not different from CON (p>0.05), but capillary to fibre ratio was lower in MCT (1.93±0.07 vs. 1.65±0.09; p=0.03). Furthermore, SDH-activity was 15% lower in MCT (OD: 0.27±0.02 vs. 0.22±0.02; p=0.048) and accompanied by a 16% lower mitochondrial oxygen consumption with pyruvate, malate and glutamate (5.7±1.5 vs. 4.8±1.3 pmol O2.s-1.mg-1; p=0.08), a 31% lower ADP-stimulated respiration (24.3±5.4 vs. 16.8±5.3 pmol O2.s-1.mg-1; p=0.01), but a similar (p=0.83) oxygen flux following complex I inhibition by rotenone. The lower responsiveness of skeletal muscle oxygen consumption to ADP, that was attenuated using a complex I inhibitor, suggests mitochondrial complex I dysfunction in HF. This, together with lower muscle capillarity and mitochondrial density, is consistent with the lower peak oxygen uptake and slower oxygen uptake kinetics observed in HF patients. That these changes are observed without a major change in skeletal muscle fibre type suggests that structural and functional adaptations in oxygen supply and utilisation are among the initial skeletal muscle adaptations occurring in HF.

Where applicable, experiments conform with Society ethical requirements