Paracrine effects of IGF-1 overexpression on the functional decline due to skeletal muscle disuse: molecular and functional evaluation in hindlimb unloaded MLC/mIgf-1 transgenic mice

Slow-twitch muscles, functionally devoted to postural maintenance, experience atrophy and weakness during muscle disuse due to different conditions such as bed-rest and immobilization, aging or spaceflight. These situations can impair motion activities and, in severe cases, have survival consequences. Accumulating evidence in human and animal studies demonstrates the anabolic role of IGF-1 on skeletal muscle suggesting its interest in muscle disuse countermeasure. To evaluate the effects of IGF-1 in the disuse-induced muscle changes, we applied the hindlimb unloading (HU) model to MLC/mIgf-1 transgenic mice that express IGF-1 under the transcriptional control of MLC promoter, selectively activated in (fast-twitch?) muscle fibers. In the present study, HU produced atrophy to soleus muscle, in terms of reduction in weight and muscle fiber cross-sectional area (CSA), and up-regulation of the atrophy gene MuRF1. In addition, HU caused a slow-to-fast phenotype transition, as demonstrated by a decrease of the slow myosin heavy chain (MHC) isoform and an increase of fast isoforms, paralleled by a decrease of slow type 1 fibers and an increase of type 2A. Consistent with the slow-to-fast transformation, HU caused a coherent transformation of contractile properties in soleus muscle, as well as the increase of resting chloride conductance (gCl) and ClC-1 expression, the decrease of the resting intracellular calcium level lowered, and the increase of PGC-1α expression, a marker of disuse-induced fiber switching, and the increase of histone deacetylase-5 (HDAC5), expressed in the fast-fibers. IGF-1 overexpression was unable to counter the loss of soleus muscle weight, the decrease of fiber CSA, and the up-regulation of atrophy-related genes in transgenic mice exposed to 14-days of HU. However, IGF-1 overexpression prevented the changes of contractile parameters and the increase of gCl induced by HU. These results indicate that IGF-1, while has earlier effects in the amelioration of muscle atrophy, can prevent the HU-induced modification of important functional parameters.