HEART-FAILURE IN RATS CAUSES CHANGES IN SKELETAL-MUSCLE MORPHOLOGY AND GENE-EXPRESSION THAT ARE NOT EXPLAINED BY REDUCED ACTIVITY

In patients with congestive heart failure, skeletal muscle is characte rized by a smaller proportion of slow-twitch oxidative fibers and redu ced oxidative enzyme activity. However, whether these changes result f rom disuse or occur as a direct consequence of heart failure is unreso lved. To address this issue, 18 rats with heart failure 8 weeks after left coronary artery ligation and 13 sham-operated control rats underw ent quantification of locomotor activity by a photocell activation tec hnique, measurements of hemodynamics and infarct size, histochemical a nd morphological analyses of the soleus and plantaris muscles, and Nor thern analyses of muscle contractile protein and oxidative enzyme mRNA expression. Although the rats with heart failure had elevated left ve ntricular end-diastolic pressures (24.1+/-2.6 mm Hg) and a mean infarc t size of 35.1+/-4.1%, activity levels were similar to those found in the sham-operated rats (3849+/-304 versus 3526+/-130 counts per hour). With heart failure, there was a significant reduction of type I fiber s in the soleus muscle and type IIa fibers in the plantaris muscle, wi th corresponding increases in intermediate staining of type IIab fiber s in both muscles. This was associated with a 17% decrease in citrate synthase activity in both the soleus and plantaris muscles (26.2+/-1.6 Versus 30.7+/-3.4 and 29.1+/-2.4 versus 35.7+/-3.4 mu mol/L per minut e per gram, respectively [P<.05]). In the soleus muscle, mRNA for both beta-myosin heavy chains and cytochrome C oxidase LU (normalized to 1 8S RNA) was reduced (0.271+/-0.02 versus 0.65+/-0.02 and 0.23+/-0.04 v ersus 0.64+/-0.02 U), whereas the messages for IIx and IIb myosin heav y chains were increased. A similar decrease in messages for cytochrome oxidase and the primary myosin isoform was observed in the plantaris muscle. Both soleus beta-myosin heavy chain and cytochrome C oxidase e xpression show significant inverse relationships to left ventricular e nd-diastolic pressure and infarct size. In contrast, there was no rela tionship between either beta-myosin heavy chain or cytochrome C oxidas e expression and locomotor activity. These results indicate that in ra ts heart failure produces changes in skeletal muscle gene expression a t the pretranslational level that cannot be explained by inactivity.