Skeletal muscle fibres synthesis in heart failure: role of PGC-1alpha, 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-1alpha, 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-1alpha.


METHODS
We investigated the levels of PGC-1alpha 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-1alpha 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-1alpha 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-1alpha plays an important role in regulating slow fibres expression. PGC1-1alpha 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.
Vescovo
Giorgio
G
Internal Medicine, City Hospital, Vicenza, Italy.
Ravara
Barbara
B
Gobbo
Valerio
V
Angelini
Annalisa
A
Dalla Libera
Luciano
L
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D019703:Calcineurin / Q000502:physiology; D045304:Cytochromes c / Q000378:metabolism; D006333:Heart Failure / Q000209:etiology / Q000378:metabolism* / Q000503:physiopathology; D006360:Heat-Shock Proteins / Q000502:physiology; D019382:Human Growth Hormone / Q000008:administration & dosage / Q000502:physiology; D006976:Hypertension, Pulmonary / Q000150:complications / Q000378:metabolism / Q000503:physiopathology; D007150:Immunohistochemistry; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D008297:Male; D018485:Muscle Fibers, Skeletal / Q000187:drug effects / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism*; D018995:Myosin Heavy Chains / Q000378:metabolism; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D020033:Protein Isoforms / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D014157:Transcription Factors / Q000502:physiology; D019210:Troponin I / Q000378:metabolism
D006360:Heat-Shock Proteins; C486497:PPARGC1A protein, human; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D020033:Protein Isoforms; D014157:Transcription Factors; D019210:Troponin I; D019382:Human Growth Hormone; D007334:Insulin-Like Growth Factor I; D045304:Cytochromes c; D019703:Calcineurin; D018995:Myosin Heavy Chains