© 1996 American Heart Association, Inc.
Articles |
Heart Failure in Rats Causes Changes in Skeletal Muscle Morphology and Gene Expression That Are Not Explained by Reduced Activity
the Department of Medicine (C.S.L., B.M.M.), Cardiovascular Research Institute (A.S., C.S.L., P.Y., B.M.M.), and Clinical Pharmacology Division (A.S.) of the University of California, San Francisco; the Cardiology Section (B.M.M., C.S.L.) of the Department of Veterans Affairs Medical Center, San Francisco, Calif; and the Department of Exercise Science (J.M., G.A.D.), the University of Georgia, Athens.
Correspondence to Barry M. Massie, MD, Cardiology Section (111C), Veterans Affairs Medical Center, 4150 Clement St, San Francisco, CA 94121. E-mail massie.barry@sanfrancisco.va.gov.
In patients with congestive heart failure, skeletal muscle is characterized by a smaller proportion of slow-twitch oxidative fibers and reduced oxidative enzyme activity. However, whether these changes result from disuse or occur as a direct consequence of heart failure is unresolved. To address this issue, 18 rats with heart failure 8 weeks after left coronary artery ligation and 13 sham-operated control rats underwent quantification of locomotor activity by a photocell activation technique, measurements of hemodynamics and infarct size, histochemical and morphological analyses of the soleus and plantaris muscles, and Northern analyses of muscle contractile protein and oxidative enzyme mRNA expression. Although the rats with heart failure had elevated left ventricular end-diastolic pressures (24.1±2.6 mm Hg) and a mean infarct 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 fibers in the soleus muscle and type IIa fibers in the plantaris muscle, with corresponding increases in intermediate staining of type IIab fibers 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 µmol/L per minute per gram, respectively [P<.05]). In the soleus muscle, mRNA for both ß-myosin heavy chains and cytochrome C oxidase III (normalized to 18S RNA) was reduced (0.27±0.02 versus 0.65±0.02 and 0.23±0.04 versus 0.64±0.02 U), whereas the messages for IIx and IIb myosin heavy chains were increased. A similar decrease in messages for cytochrome oxidase and the primary myosin isoform was observed in the plantaris muscle. Both soleus ß-myosin heavy chain and cytochrome C oxidase expression show significant inverse relationships to left ventricular end-diastolic pressure and infarct size. In contrast, there was no relationship between either ß-myosin heavy chain or cytochrome C oxidase expression and locomotor activity. These results indicate that in rats heart failure produces changes in skeletal muscle gene expression at the pretranslational level that cannot be explained by inactivity.
Key Words: heart failure • skeletal muscle • fiber types • gene expression • locomotor activity
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