The molecular function of MuRF1 and its stability in skeletal muscle

Musa, Ibrahim (2023). The molecular function of MuRF1 and its stability in skeletal muscle. University of Birmingham. Ph.D.

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Abstract

Skeletal muscle mass is essential for the maintenance of metabolic function. The amount of skeletal muscle mass depends on the net balance between muscle protein synthesis (MPS) and muscle protein breakdown (MPB). Skeletal muscle atrophy occurs when MPB exceeds MPS. MuRF1 (Muscle-specific ubiquitin ring finger 1), an E3 ligase, is a valid marker of skeletal muscle atrophy. However, its precise molecular
function in the control of skeletal muscle mass is currently unclear. The present thesis establishes and addresses the gaps in the body of knowledge that, if addressed, may advance the knowledge of skeletal muscle mass regulation at molecular and cellular levels. MuRF1 is important in the degradation of muscle proteins, but recent studies suggest that it may also regulate a range of other non-degradative cellular processes. Herein, after making MuRF1 reporter and functional deficiency skeletal muscle cell lines, our data provide first evidence that MuRF1 regulates skeletal muscle mass by increasing muscle insulin resistance and inhibiting protein synthesis by upregulating the expression of TRIM72 protein. In addition, employing an ubiquitin-TUBE pulldown strategy, we have demonstrated that MuRF1 undergoes auto-ubiquitylation to regulate its own stability in skeletal muscle via K48- and K63- poly-ubiquitin chains signal. MuRF1 auto-ubiquitylation-mediated K48- and K63-poly-ubiquitin chains signal proteasomal and autophagy-mediated auto-degradation of MuRF1. Importantly, a novel two-step mechanism of MuRF1 auto-ubiquitylation was demonstrated in vitro, where recombinant MuRF1 first undergoes auto-mono-ubiquitylation in the presence of UBE2W, which in turn, convert into anchored poly-ubiquitin chains with further addition of UBE2D2 and UBE2N/V1, or UBE2N/V2, respectively. Overall, this thesis advances our understanding of MuRF1's mechanistic role and regulation in skeletal muscle. Our novel findings have provided new directions for further exploration of the role of MuRF1 in the regulation of skeletal muscle mass

Type of Work:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

Supervisor(s):