Dual influence of disease and increased load on diaphragm muscle in heart failure

We have recently shown that mitochondrial function and energy metabolism ar e altered in the myocardium as well as in slow and fast locomotor muscles o f rats subjected to prolonged congestive heart failure (CHF) suggesting a g eneralized metabolic myopathy in heart failure, Here, we investigate whethe r the diaphragm of CHF animals, which experiences both increased work and t he general systemic influence of heart failure, will also be susceptible to altered energy metabolism Biopsies were obtained from the costal diaphragm of failing rats 8 months after aortic banding. A marked increase in type I and type IIa myosin heavy chains at the expense of types IIx and IIb, sugg ests an adaptation towards a slower phenotype. Glycolytic enzymes decreased in CHF diaphragm with an increase in the H:M lactate dehydrogenase isoenzy me ratio. These results suggest a reorientation of the diaphragm muscle tow ards a slow fatigue-resistant phenotype. However, maximal oxidative capacit y assessed in saponin-permeabilized fibers in the presence of ADP was consi derably reduced in CHF diaphragm (7.7 +/- 0.4 v 11.8 +/- 0.7 mu mol O-2/min /g dry weight in sham: P<0.001), suggesting an alteration in oxidative phos phorylation. Furthermore, ADP sensitivity of CHF mitochondria was significa ntly increased (apparent k(m) for ADP 308 <plus/minus> 21 v 945 +/- 106 muM in sham; P<0.001), whereas sensitivity to ADP in the presence of creatine was comparable (K-m 79 <plus/minus> 12 v 90 +/- 11 in sham). In heart failu re, therefore, the diaphragm muscle seems to adapt towards a more slow and economical contraction as a result of increased workload, but this adaptati on is limited by the disease-induced altered mitochondrial function. (C) 20 01 Academic Press.