Biliary cirrhosis induces type IIx/b fiber atrophy in rat diaphragm and skeletal muscle, and decreases IGF-I mRNA in the liver but not in muscle

Abstract

Background/aims: Patients with cirrhosis complain of fatigue, which in part may be due to the progressive muscle atrophy, noted especially when signs of decompensation appear. In addition, weaning from mechanical ventilation may be difficult in some patients following liver transplantation. Since little is known about the peripheral muscles and the diaphragm in cirrhosis, we investigated diaphragm and gastrocnemius histochemical properties, and diaphragm contractile properties in male rats with biliary cirrhosis. In addition, the extent to which insulin-like growth factor I (IGF-I) was involved in the regulation of muscle function was also examined, since IGF-I is known to induce growth and regeneration as well as to exert a protein anabolic action.

Methods: Ten rats underwent a sham operation, while another ten underwent bile duct ligation and excision. After 5 weeks, biliary cirrhosis was confirmed histologically in random liver biopsies.

Results: Compared to sham animals, diaphragm mass in cirrhotic rats was decreased by 10% (p<0.05), while masses of other respiratory (e.g. scalenus medius -21%, p<0.001) or peripheral muscles (e.g. gastrocnemius -24%, p<0.0001) decreased more. No changes in diaphragm force nor in its endurance were observed between the two groups. However, a clear decrease in the cross-sectional area of type IIx/b muscle fiber was present in both diaphragm (1360+/-147 vs 1112+/-167 microm2, p<0.02) and gastrocnemius (1954+/-265 vs 2328+/-245 microm2, p<0.02). Finally, hybridization of Northern blot with a rat cDNA IGF-I probe (gift from Dr D. Leroith, Bethesda, USA) labeled with alpha-32P revealed that in cirrhotic rats, the relative expression of IGF-I was markedly reduced by 45% in the liver (p<0.05) but was unchanged in the two muscles studied.

Conclusions: In this model of biliary cirrhosis: (i) muscle wasting was less pronounced in the diaphragm than in other muscles; (ii) type IIx/b fiber atrophy in respiratory (diaphragm) and peripheral muscles (gastrocnemius) developed while diaphragm contractile properties remained unchanged; and (iii) the relative expression of IGF-I was reduced in the liver only, while it remained unchanged in the muscle. The functional significance of these changes, their pathogenesis and presence in other models and in human cirrhosis remain to be elucidated.