BILIARY-CIRRHOSIS INDUCES TYPE IIX B FIBER ATROPHY IN RAT DIAPHRAGM AND SKELETAL-MUSCLE, AND DECREASES IGF-I MESSENGER-RNA IN THE LIVER BUTNOT IN MUSCLE/

Background/Aims: Patients with cirrhosis complain of fatigue, which in part may be due to the progressive muscle atrophy, noted especially w hen signs of decompensation appear. In addition, weaning from mechanic al ventilation may be difficult in some patients following liver trans plantation. Since little is known about the peripheral muscles and the diaphragm in cirrhosis, we investigated diaphragm and gastrocnemius h istochemical 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 web as to exert a protein anabolic action. Methods: Te n rats underwent a sham operation, while another ten underwent bile du ct ligation and excision. After 5 weeks, biliary cirrhosis was confirm ed 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<0.0 01) or peripheral muscles (e.g. gastrocnemius -24%, p<0.0001) decrease d more. No changes in diaphragm force nor in its endurance were observ ed between the two groups. However, a clear decrease in the cross-sect ional area of type IIx/b muscle fiber was present in both diaphragm (1 360+/-147 vs 1112+/-167 mu m(2), p<0.02) and gastrocnemius (1954+/-265 vs 2328+/-245 mu m(2), p<0.02). Finally, hybridization of Northern bl ot with a rat cDNA IGF-I probe (gift from Dr D. Leroith, Bethesda, USA ) labeled with alpha-(32)p revealed that in cirrhotic rats, the relati ve expression of IGF-I was markedly reduced by 45% in the liver (p<0.0 5) 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) develop ed while diaphragm contractile properties remained unchanged; and (iii ) the relative expression of IGF-I was reduced in the liver only, whil e 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.