Apoptosis of skeletal muscle myofibers and interstitial cells in experimental heart failure

Congestive heart failure (CHF) is characterized by a limb skeletal muscle m yopathy with shift from the slow aerobic, fatigue resistant fibers, to the fast, anaerobic ones, and muscle bulk loss. Apoptosis (A) has been recently demonstrated to play a role in several cardiovascular diseases. Aim of the study: we have investigated the role of A in the skeletal muscle of the hi ndlimbs in an experimental model of CHF, Animals and methods: CHF was induc ed in 7 males 80-100 g Sprague-Dawley rats with 30 mg/kg monocrotaline. Fiv e age and diet matched controls were also studied. The time course of A was also studied in additional animals at day 0, 17, 24 and 30 days. Results: At day 27 the electrophoretic analysis of myosin heavy chains (MHCs) demons trated in the CHF rats the occurrence of a myopathy, with disappearance of slow MHC1 in the Tibialis Anterior (TA), and a significant shift from the s low to the fast isoforms in the soleus and EDL. With in situ DNA nick-end l abelling (TUNEL) we found in the TA of CHF animals a significantly higher n umber of TUNEL positive nuclei (0.43 +/- 0.24 v 0.08 +/- 0.02, P<0.02 and T UNEL positive myonuclei (0.031 +/- 0.012 v 0.0025 +/- 0.005, P<0.02). The t ime course of A showed a progressive rise in interstitial and myocyte A, ac companied by a drop in fibers cross-sectional area and muscle weight/body w eight, that came out to be significant at 30 days. Western blot showed a lo wer expression of Bcl-2 at 27 days and a further drop at 30 days in the CHF rats. Double staining for TUNEL and antibody against anti-MHC2a and anti M HC2b + 2x showed that A occurs non-selectively in all the myofiber types. b eta ANP and Right Ventricle Mass/Volume (RVM/V) correlated significantly wi th total apoptotic nuclei. Conclusions: In CHF myofibers A can lead to musc le atrophy. Endothelial cells A may produce an imbalance in myofibres nutri tion with relative ischemia that triggers the preferential synthesis of fas t anaerobic myosin as an adaptive mechanism or alternatively induce myofibr es death. (C) 1998 Academic Press.