Homer 2 antagonizes protein degradation in slow-twitch skeletal muscles.

The presence of Homer isoforms, referable to 1b/c and 2a/b, was investigated in fast- and slow-twitch skeletal muscles from both rat and mouse. Homer 1b/c was identical irrespective of the muscle, Homer 2a/b was instead characteristic of the slow-twitch phenotype. Transition in Homer isoform composition was studied in two established experimental models of atrophy, i.e., denervation and disuse of slow-twitch skeletal muscles of the rat. No change of Homer 1b/c was observed, whereas Homer 2a/b was found to be significantly decreased at 7 and 14 days after denervation by 70% and 90%, and in parallel to reduction of muscle mass; 3 days after denervation, relative mRNA was reduced by 90% and remained low thereafter. Seven-day hind-limb suspension decreased Homer 2a/b protein by 70%. Reconstitution of Homer 2 complement by in vivo transfection of denervated soleus, allowed partial rescue of the atrophic phenotype, as far as muscle mass, muscle fiber size and ubiquitinazion is concerned. The counteracting effects of exogenous Homer 2 were mediated by down-regulation of MuRF1, Atrogin and Myogenin, i.e., all genes known to be up-regulated at the onset of atrophy. On the other hand, slow-to-fast transition of denervated soleus was not rescued by Homer 2 replacement. Down-regulation of Homer 2 is deemed an early event of atrophy, and Homer 2 participates in the control of ubiquitinization and ensuing proteolysis via transcriptional down-regulation of MuRF1, Atrogin and Myogenin. Homers are key players of skeletal muscle plasticity and Homer 2 is required for trophic homeostasis of slow-twitch skeletal muscles.