OVER-EXPRESSION OF IGF-I IN SKELETAL MUSCLE DOES NOT PREVENT UNLOADING-INDUCED ATROPHY 385

Abstract

This study examined the hypothesis that high level local expression of insulin-like growth factor I (IGF-I) in skeletal muscle would prevent or minimize unloading-induced atrophy. We employed transgenic mice in which the-424 promoter, first intron and 3' untranslated region of the avian skeletal alpha actin gene drives expression of human IGF-I. Expression of the transgene results in -47 fold increase in IGF-I concentration specific to skeletal muscle (J. Biol. Chem. 270: 12109-12116, 1995). Male transgenic mice and non-transgenic mice from the parent strain (FVB) were divided into four groups (n = 10/group): 1) Transgenic, weight-bearing (IGF-I/WB); 2) transgenic, hindlimb unloaded (IGF-I/HU); 3) non-transgenic, weight-bearing(FVB/WB); and 4) non-transgenic, hindlimb unloaded (FVB/HU). HU groups were tail suspended for 14 days. Body mass was reduced (P<0.05) following HU in both IGF-I (-9%) and FVB mice (-13%). Mass of the gastrocnemius (GAST) and tibialis anterior (TA) muscles were reduced (p<0.05) in both FVB/HU and IGF-I/HU groups compared to FVB/WB and IGF-I/WB, respectively. The percent atrophy of mass in the GAST and TA following HU did not differ between IGF-I and FVB mice. Elevated expression of IGF-I mRNA was confirmed in the GAST and TA of the transgenic mice. However, HU resulted in a marked reduction in transgene expression in these muscles (although still much greater than FVB mice). Further, transgene expression was found to be undetectable in the soleus of transgenic mice. Therefore, high level local expression of IGF-I in skeletal muscle does not prevent unloading-induced skeletal muscle atrophy. Also, the avian skeletal alpha actin regulatory sequences used to drive this transgene confer fiber-type specific expression of human IGF-I and are sensitive to loading of the muscles.