Skeletal muscle fibres synthesis in heart failure: Role of PGC-1α, 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 II fibres, fast MHCs and muscle atrophy. PGC-1α, 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-1α. Methods We investigated the levels of PGC-1α 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-1α 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-1α 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-1α plays an important role in regulating slow fibres expression. PGC1-1α 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.