Atrophy-related ubiquitin ligases, atrogin-1 and MuRF1 are up-regulated in aged rat Tibialis Anterior muscle

Abstract

A phenotypic feature of aging is skeletal muscle wasting. It is characterized by a loss of muscle mass and strength. Age-related loss of muscle mass occurs through a reduction in the rate of protein synthesis, an increase in protein degradation or a combination of both. However, the underlying mechanism is still poorly understood. To test the hypothesis that the ubiquitin-proteasome pathway contributes to this phenomenon, we studied MuRF1 and atrogin-1 expression in Tibialis Anterior muscle of aged rats. These two E3 ligases are considered as sensitive markers of muscle protein degradation by the ubiquitin-proteasome system. Our results revealed that, in skeletal muscle of aged rats, the decline in muscle mass is accompanied by an increase in the level of oxidized proteins and ubiquitin conjugates (90%) whereas the functionality of the proteasome remains constant compared to young rats. Furthermore, the level of both MuRF1 and atrogin-1 mRNA is markedly up-regulated in aged muscle (respectively x2 and x2.5). Taken together these data argue for the involvement of the ubiquitin-proteasome pathway in sarcopenia of fast-twitch muscle, in particular through increased expression of MuRF1 and atrogin-1. Moreover, we observed a decrease in the IGF-1/Akt signalling pathways and elevated level of TNFalpha mRNA in aged rat muscle. Therefore, IGF-1/Akt and TNFalpha represent potential mediators implicated in the regulation of MuRF1 and atrogin-1 genes during aging.