MuRF1/TRIM63, Master Regulator of Muscle Mass

Figures

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  Figure 1. MuRF1 structure and known regions of interaction with some partners. MuRF1 structure is characterized by a RBCC (RING-B-box-coiled-coil) motif constituted by an N-terminal RING domain (23–79), a MuRF family specific motif (MFC) motif (79–113), a B-box type 2 (Bb2) domain (117–161), a central helical domain (166–328) with a COS-box motif (269–328) and a C-terminal acidic tail (328–353). Several regions have been identified for their interaction with MuRF1 partners (substrates in dark blue and other interactors in light blue): Titin [2], cardiac troponin I [21,28], muscle-type creatine kinase (MCK) [29], c-Jun [22], the ubiquitin conjugating enzymes (UBE2s) [30], CARP 119–325 [31]. HD, helical domain.

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  Figure 2. Transcriptional Regulation of MuRF1. (a) Pathways that control MuRF1 transcription. MuRF1 transcription is regulated by different stimuli that activate several signaling pathways, and several different transcription activators and repressors. See main text for further details. GR, glucocorticoid receptor, PM, plasma membrane. (b) The promoter of the mouse (C57BL/6J) MuRF1 gene is schematically shown with the transcription factors potentially promoting or interfering with MuRF1 transcription in the skeletal muscle. Binding sites are numbered starting with the transcription initiation as base +1. Only the sites experimentally tested are shown but several other potential sites exist in the promoter sequence for most of them. For the repressor Zeb1, 30 other sites exist but they have not been individually tested and only the ones present in the proximal region of the promoter are shown. In the heart, the activity of a MEF2 binding site (−32/−23) encompassing the proximal FoxO site was reported.

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  Figure 3. MuRF1 functions in skeletal muscle. MuRF1 is responsible for the coordinated breakdown of both thick and thin filament occurring during catabolic states in skeletal muscle. Like in cardiac muscle, MuRF1 probably binds to titin at the M-line in some conditions (catabolic conditions, MuRF1 excess, etc.), causing the disruption of titin/M-line interactions and hence a partial disorganization of sarcomere assembly. Upon sarcomere destabilization, MuRF1 would have access to contractile proteins (alpha-actin, troponins I, C, and T, MHC, MLC, MyBP-C), to target them for polyUb and proteasome-dependent degradation. MuRF1 also drives telethonin (Tcap) degradation, but it remains to determine which form of the telethonin is targeted by MuRF1: The free form, the titin-complexed form, or both. The inhibition of protein synthesis by MuRF1 has been reported in skeletal muscles, but more investigations are needed to confirm this role. MuRF1 was reported to target the non-functional oxidized form of muscle creatine kinase (O-MCK). CHRN is targeted to the LC3-II-positive autophagosome for selective autophagy under catabolic condition. This process is regulated and/or mediated partly by MuRF1 and…

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  Figure 4. MuRF1 functions in cardiac muscle. MuRF1 exhibits a protective role in the heart by inhibiting pathological heart hypertrophy. Anti-hypertrophic function of MuRF1 can partly be explained by its atrophic function and the degradation of sarcomeric proteins like in skeletal muscle. Moreover, MuRF1 inhibits the protein synthesis of hypertrophy-related genes in response to hypertrophic stimuli, via the inhibition of at least three pathways (serum response factor (SRF), c-Jun N-terminal kinases (JNK), and AKT pathways). The activation of calcineurin/NFAT (nuclear factor of activated T cells) signaling alone is sufficient to induce pathological cardiac hypertrophy. MuRF1, by down-regulating the phosphatase CnA, prevents the translocation of the nuclear factor NFAT transcription from the cytosol to the nucleus and thus the consecutive transcription of hypertrophy-related genes. Moreover, MuRF1 mediates the inhibition of PKCε translocation to focal adhesions, a critical event in the hypertrophic signaling cascade. MuRF1 also limits physiological cardiac hypertrophy by inhibiting c-Jun protein expression and phosphorylation in the presence of insulin-like growth factor 1 (IGF-1). Another…