Dual influence of disease and increased load on diaphragm muscle in heart failure. 
We have recently shown that mitochondrial function and energy metabolism are altered in the myocardium as well as in slow and fast locomotor muscles of rats subjected to prolonged congestive heart failure (CHF) suggesting a generalized metabolic myopathy in heart failure.  Here, we investigate whether the diaphragm of CHF animals, which experiences both increased work and the 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, suggests an adaptation towards a slower phenotype.  Glycolytic enzymes decreased in CHF diaphragm with an increase in the H:M lactate dehydrogenase isoenzyme ratio.  These results suggest a reorientation of the diaphragm muscle towards a slow, fatigue-resistant phenotype.  However, maximal oxidative capacity assessed in saponin-permeabilized fibers in the presence of ADP was considerably reduced in CHF diaphragm (7.7+/-0.4 v 11.8+/-0.7 micromol O2/min/g dry weight in sham P<0.001), suggesting an alteration in oxidative phosphorylation.  Furthermore, ADP sensitivity of CHF mitochondria was significantly increased (apparent Km for ADP 308+/-21 v 945+/-106 microM in sham P<0.001), whereas sensitivity to ADP in the presence of creatine was comparable (Km 79+/-12 v 90+/-11 microM in sham).  In heart failure, therefore, the diaphragm muscle seems to adapt towards a more slow and economical contraction as a result of increased workload, but this adaptation is limited by the disease-induced altered mitochondrial function.