Abstract

Skeletal muscle atrophy is a common consequence of chronic heart failure. Although the extent of muscle atrophy due to chronic heart failure greatly impacts functional capacity, the mechanisms responsible for heart failure-induced muscle atrophy are not established. The protein kinase B (PKB)/mammalian target of rapamycin (mTOR) signaling pathway plays a predominant role in regulating skeletal muscle size by controlling mRNA translation initiation and protein synthesis. Whether or not a decline in the activity of the PKB/mTOR signaling pathway is associated with heart failure-induced muscle atrophy is unknown. PURPOSE To determine if the muscle atrophy observed in chronic heart failure is associated with decreases in the activity of the PKB/mTOR signaling pathway. METHODS Female Wistar rats (∼315 g) were subjected to a sham operation or the coronary artery was ligated to produce either a moderate (MOD) myocardial infarction or a severe (SEV) myocardial infarction. Eight weeks following the sham operation or coronary artery ligation the right carotid artery was cannulated with a 2-Fr catheter-tip pressure manometer to measure left ventricular end diastolic pressure (LVEDP). The total amounts and activity of PKB, mTOR, and S6 kinase 1 (S6K1) were assessed in plantaris muscle extracts by immuno-blotting with antibodies specific to the respective signaling proteins. The weight of the plantaris muscle was also assessed to determine the degree of muscle atrophy due to heart failure. RESULTS LVEDP was 4.8 fold higher in rats subjected to a SEV myocardial infarction compared to rats subjected to a MOD myocardial infarction (22.9 ± 4.8 vs. 4.74 ± 0.5 mmHg, p = 0.0004) indicating the presence of severe heart failure. LVEDP was not significantly different between rats subjected to a MOD myocardial infarction compared to rats subjected to a sham operation (4.74 ± 0.5 vs. 2.36 ± 0.3 mmHg). The mass of the plantaris muscle was significantly lower in rats subjected to a SEV myocardial infarction compared to rats subjected to a MOD myocardial infarction or a sham operation (SEV: 354.4+40.7 vs. MOD: 500.4+13.2 vs. CON: 445.2+2.1 mg, p = 0.009) demonstrating that severe heart failure resulted in muscle atrophy. Despite the marked decline in plantaris muscle mass, the total amounts and the activity of PKB, mTOR, and S6K1 were not altered by severe heart failure. CONCLUSIONS These findings indicate that muscle atrophy associated with chronic severe heart failure is independent of the PKB/mTOR signaling pathway.

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