Regional skeletal muscle remodeling and mitochondrial dysfunction in right ventricular heart failure

Wust RC, Myers DS, Stones R, Benoist D, Robinson PA, Boyle JP, Peers C, White E, Rossiter HB. Regional skeletal muscle remodeling and mitochondrial dysfunction in right ventricular heart failure. Am J Physiol Heart Circ Physiol 302: H402-H411, 2012. First published October 28, 2011; doi: 10.1152/ajpheart.00653.2011.-Exercise intolerance is a cardinal symptom of right ventricular heart failure (RV HF) and skeletal muscle adaptations play a role in this limitation. We determined regional remodeling of muscle structure and mitochondrial function in a rat model of RV HF induced by monocrotaline injection (MCT; 60 mg.kg(-1); n = 11). Serial sections of the plantaris were stained for fiber type, succinate dehydrogenase (SDH) activity and capillaries. Mitochondrial function was assessed in permeabilized fibers using respirometry, and isolated complex activity by blue native gel electrophoresis (BN PAGE). All measurements were compared with saline-injected control animals (CON; n = 12). Overall fiber cross-sectional area was smaller in MCT than CON: 1,843 +/- 114 vs. 2,322 +/- 120 mu m(2) (P = 0.009). Capillary-to-fiber ratio was lower in MCT in the oxidative plantaris region (1.65 +/- 0.09 vs. 1.93 +/- 0.07; P = 0.03), but not in the glycolytic region. SDH activity (P = 0.048) and maximal respiratory rate (P = 0.012) were each similar to 15% lower in all fibers in MCT. ADP sensitivity was reduced in both skeletal muscle regions in MCT (P = 0.032), but normalized by rotenone. A 20% lower complex I/IV activity in MCT was confirmed by BN PAGE. MCT-treatment was associated with lower mitochondrial volume density (lower SDH activity), quality (lower complex I activity), and fewer capillaries per fiber area in oxidative skeletal muscle. These features are consistent with structural and functional remodeling of the determinants of oxygen supply potential and utilization that may contribute to exercise intolerance and reduced quality of life in patients with RV HF.