Skeletal muscle fibers synthesis in heart failure: role of PGC-1 alpha, calcineurin and GH

Background: Patients with congestive heart failure (CHF) have decreased exercise capacity because of muscle fatigability. Symptoms are due to a specific myopathy with increased expression of fast type 11 fibres, fast MHCs and muscle atrophy. PGC-1 alpha, a potent transcriptional coactivator for nuclear receptors, induces mitochondrial myogenesis and the preferential synthesis of slow fibres. IGF1-Calcineurin stimulation can lead to increased expression of PGC-1 alpha. Methods: We investigated the levels of PGC-1 alpha during progression and regression of skeletal myopathy in the soleus muscle of rats with right heart failure secondary to monocrotaline-induced pulmonary hypertension. We used GH to stimulate the IGF1-calcineurin-PGC-1 alpha axis. Results: The slow MHC1 decreased from 90.6 +/- 0.5 to 71.7 +/- 2.2 in the CHF rats (p<0.00001) and increased to 82.1 +/- 1.8 after GH (p<0.00002). Western blot analysis showed that PGC-1 alpha is significantly decreased in CHF, while it came back to control values after GH. Cytochrome c was decreased in CHF and returned to control values with GH. Troponin I was expressed solely as slow isoform in the control soleus, while the fast isoform appeared in CHF. Its expression returned to control values after GH. Conclusions: We conclude that PGC-1 alpha plays an important role in regulating slow fibres expression. PGC1-1 alpha is in turn regulated by the IGF1-calcineurin axis. GH by increasing the circulating levels of IGF1, enhanced the expression of slow MHC1, TnI and the synthesis of mitochondria. (c) 2005 Elsevier Ireland Ltd. All rights reserved.