Skeletal muscle atrophy and the E3 ubiquitin ligases MuRF1 and MAFbx/atrogin-1

Abstract

Muscle RING finger 1 (MuRF1) and muscle atrophy F-box (MAFbx)/atrogin-1 were identified more than 10 years ago as two muscle-specific E3 ubiquitin ligases that are increased transcriptionally in skeletal muscle under atrophy-inducing conditions, making them excellent markers of muscle atrophy. In the past 10 years much has been published about MuRF1 and MAFbx with respect to their mRNA expression patterns under atrophy-inducing conditions, their transcriptional regulation, and their putative substrates. However, much remains to be learned about the physiological role of both genes in the regulation of mass and other cellular functions in striated muscle. Although both MuRF1 and MAFbx are enriched in skeletal, cardiac, and smooth muscle, this review will focus on the current understanding of MuRF1 and MAFbx in skeletal muscle, highlighting the critical questions that remain to be answered.

Uncoupling protein 1 expression in adipocytes derived from skeletal muscle fibro/adipogenic progenitors is under genetic and hormonal control

“…To this end, 18 months old Sv/129 female mice received intramuscular injections of GLY into the TA and were compared with younger mice (3 months old). While TA muscle weight was not significantly affected by age (data not shown), aged muscle expressed higher levels of the two muscle‐specific E3 ubiquitin ligases muscle RING finger 1 and muscle atrophy F‐box (Atrogin‐1), which are reportedly increased during muscle atrophy at the transcriptional level45 ( Figure 7). Importantly, intramuscular GLY injections induced an up‐regulation of Pparg2 and Ucp1 mRNA levels to the same extent in TA muscles of young and aged mice ( Figure 7).…”

Paradoxical effect of IKKβ inhibition on the expression of E3 ubiquitin ligases and unloading-induced skeletal muscle atrophy

“…2015). In addition to FoxO several other transcription factors can influence expression of E3 ubiquitin ligases (Bodine and Baehr 2014). For example, myogenin can activate MURF‐1 and MAFbx expression during muscle atrophy caused by denervation (Moresi et al.…”

“…2013; Bodine and Baehr 2014). Skeletal muscle‐specific E3 ubiquitin ligases MuRF1 and MAFbx are upregulated during unloading‐induced muscle atrophy.…”

Small‐molecule inhibition of MuRF1 attenuates skeletal muscle atrophy and dysfunction in cardiac cachexia

“…atrophy), which occurs in both limb and respiratory muscles, plays a critical role in skeletal muscle weakness and respiratory complications observed in many patients, which, in turn, exacerbates symptoms and prognosis 1. The underlying mechanisms of muscle atrophy include the activation of so‐called atrogins, leading to an enhanced degradation of proteins via the autophagosome and ubiquitin‐proteome system2, 3, 4, 5 with muscle ring finger 1 (MuRF1) believed to provide a key step in the transfer of multi‐ubiquitinated muscle proteins to the latter system for degradation, respectively 6. Consistent with the view that MuRF1 acts as an atrogin, its expression is intimately associated with muscle wasting in numerous clinical conditions (as reviewed in Bodine and Baehr2) or following exposure to pharmacological treatments (e.g.…”

“…The underlying mechanisms of muscle atrophy include the activation of so‐called atrogins, leading to an enhanced degradation of proteins via the autophagosome and ubiquitin‐proteome system2, 3, 4, 5 with muscle ring finger 1 (MuRF1) believed to provide a key step in the transfer of multi‐ubiquitinated muscle proteins to the latter system for degradation, respectively 6. Consistent with the view that MuRF1 acts as an atrogin, its expression is intimately associated with muscle wasting in numerous clinical conditions (as reviewed in Bodine and Baehr2) or following exposure to pharmacological treatments (e.g. glucocorticoids, inflammatory cytokines, reactive oxygen species7, 8, 9, 10), while its gene inactivation confers partial resistance to muscle wasting conditions 7, 8, 11, 12.…”