Abstract
Skeletal muscle atrophy is a consequence of muscle inactivity resulting from denervation, unloading and immobility. It accompanies many chronic disease states and also occurs as a pathophysiologic consequence of normal aging. In all these conditions, ubiquitin-dependent proteolysis is a key regulator of the loss of muscle mass, and ubiquitin ligases confer specificity to this process by interacting with, and linking ubiquitin moieties to target substrates through protein∶protein interaction domains. Our previous work suggested that the ubiquitin-protein ligase Nedd4-1 is a potential mediator of skeletal muscle atrophy associated with inactivity (denervation, unloading and immobility). Here we generated a novel tool, the Nedd4-1 skeletal muscle-specific knockout mouse (myoCre;Nedd4-1flox/flox) and subjected it to a well validated model of denervation induced skeletal muscle atrophy. The absence of Nedd4-1 resulted in increased weights and cross-sectional area of type II fast twitch fibres of denervated gastrocnemius muscle compared with wild type littermates controls, at seven and fourteen days following tibial nerve transection. These effects are not mediated by the Nedd4-1 substrates MTMR4, FGFR1 and Notch-1. These results demonstrate that Nedd4-1 plays an important role in mediating denervation-induced skeletal muscle atrophy in vivo.
Highlights
Skeletal muscle atrophy is a pathophysiologic consequence of disease progression in multiple chronic illnesses such as cancer, heart failure, HIV/AIDS and endstage pulmonary disorders
To ensure that the knock-out was specific for Nedd4-1, expression of Nedd4-2 was confirmed in the Nedd4-1 SMS-KO skeletal muscle (Figure 1A)
We found that levels of both MTMR4 and Fibroblast Growth Factor Receptor 1 (FGFR1) proteins decreased in the denervated gastrocnemius muscle of control mice coincident to the increase in Nedd4-1 (Figures 7A and 7B), but there was no attenuation of that decrease for either protein in the denervated gastrocnemius of Nedd4-1 SMS-KO mice, suggesting that neither MTMR4 nor FGFR1 are substrates involved in Nedd4-1’s mediation of denervation induced muscle atrophy
Summary
Skeletal muscle atrophy is a pathophysiologic consequence of disease progression in multiple chronic illnesses such as cancer, heart failure, HIV/AIDS and endstage pulmonary disorders. Ubiquitin-mediated proteolysis was identified as a critical regulator of skeletal muscle atrophy in several animal models of disease [6,7,8]. The co-ordinated action of several enzymes (E1, E2 and E3 ubiquitin ligases) covalently attaches a single or branched ubiquitin moiety to lysine residue(s) of the target substrate protein, which can serve as a marker for regulated cellular degradation of the protein by the 26S proteasome or the lysosome [9]. The E3 ligases are the key enzymes that confer specificity to the system by binding and linking ubiquitin moieties to the substrate, often through protein:protein interaction domains [9]. There are two main families of E3 ligases; HECT (homologous to E6-AP carboxyterminus) domain E3 ligases [10] and RING (Really interesting new gene) finger ligases [11,12]
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