Homer 2 antagonizes protein degradation in slow-twitch skeletal muscles.
Homer represents a new and diversified family of proteins made up of several isoforms. 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, and 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 up to 14 days after denervation, whereas Homer 2a/b was found to be significantly decreased at 7 and 14 days after denervation by 70 and 90%, respectively, and in parallel to reduction of muscle mass; 3 days after denervation, relative mRNA was reduced by 90% and remained low thereafter. Seven-day hindlimb 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 are concerned. The counteracting effects of exogenous Homer 2 were mediated by downregulation of MuRF1, Atrogin, and Myogenin, i.e., all genes known to be upregulated at the onset of atrophy. On the other hand, slow-to-fast transition of denervated soleus, another landmark of denervation atrophy, was not rescued by Homer 2 replacement. The present data show that 1) downregulation of Homer 2 is an early event of atrophy, and 2) Homer 2 participates in the control of ubiquitinization and ensuing proteolysis via transcriptional downregulation 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.
Dipartimento di Scienze Biomediche, Università degli Studi di Padova, viale G. Colombo 3, 35121 Padova, Italy.
Elena
E
Bortoloso
Aram
A
Megighian
Sandra
S
Furlan
Luisa
L
Gorza
Pompeo
P
Volpe
D000818:Animals; D002352:Carrier Proteins / Q000502:physiology*; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000502:physiology; D000072233:Homer Scaffolding Proteins; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D018656:Muscle Fibers, Fast-Twitch / Q000378:metabolism / Q000473:pathology; D018657:Muscle Fibers, Slow-Twitch / Q000378:metabolism* / Q000473:pathology; D018482:Muscle, Skeletal / Q000294:innervation / Q000378:metabolism / Q000473:pathology; D009133:Muscular Atrophy / Q000378:metabolism / Q000473:pathology; D010641:Phenotype; D011817:Rabbits; D051381:Rats; D017208:Rats, Wistar
D002352:Carrier Proteins; D000072233:Homer Scaffolding Proteins