ALTERATIONS IN SKELETAL-MUSCLE GENE-EXPRESSION IN THE RAT WITH CHRONIC CONGESTIVE-HEART-FAILURE

Congestive heart failure is often associated with skeletal muscle abno rmalities that contribute to early fatigue and acidosis. Up to the pre sent time, however, the mechanisms responsible for these changes are u nclear. Myocardial infarctions were produced by coronary ligation in a dult Sprague-Dawley rats. At 20 weeks, 10 control rats, and 15 animals with heart failure [defined by elevated LVEDP (26.1 +/- 3.1 v 2.5 +/- 0.5 mmHg) and RV hypertrophy (300 +/- 21 g v 158 +/- 9 mg)] underwent in vivo measurements of total body, and soleus total protein and myos in heavy chain (MHC) synthesis by [H-3]leucine constant infusion. Sole us muscle was also analysed for protein content, and MHC isoenzyme con tent by SDS-PAGE. Northern blotting also was used to determine levels of the mRNA's encoding type I, IIa, IIb, and IIx MHC, alpha-skeletal a ctin, COX III, SDH and GAPDH. Soleus muscles in heart failure rats wer e smaller than controls (112 +/- 6 v 126 +/- 5 mg) and the degree of a trophy was significant when corrected for body mass (0.38 +/- 0.02 v 0 .46 +/- 0.02 mg/g, P = 0.007). Although there was no significant diffe rence in plasma leucine nux (an index of whole-body protein synthesis) , soleus muscle total and MHC synthesis was reduced in heart failure a nimals. Whereas the Type I MHC isoenzyme (beta MHC) was the only MHC d etected in the soleus of control animals, type Tr NMC isoenzyme compri sed 11.8 +/- 3.1% of the MHC in the heart failure group. Furthermore, steady-state mRNA levels encoding beta MHC were significantly depresse d in the heart failure rats, where those encoding Types IIb and IIx MH C were increased. Steady-state mRNA levels of alpha-skeletal actin, cy tochrome C oxidase (COX III) and succinate dehydrogenase (SDH) were al so significantly depressed. This animal model of chronic heart failure is associated with quantitative and qualitative alterations in skelet al muscle gene expression that are similar to those reported in skelet al muscle of patients with chronic heart failure. The altered phenotyp e and impaired metabolic capacity may contribute to exercise intoleran ce in CHF. (C) 1996 Academic Press Limited