MuRF1/TRIM63, Master Regulator of Muscle Mass

Abstract

The E3 ubiquitin ligase MuRF1/TRIM63 was identified 20 years ago and suspected to play important roles during skeletal muscle atrophy. Since then, numerous studies have been conducted to decipher the roles, molecular mechanisms and regulation of this enzyme. This revealed that MuRF1 is an important player in the skeletal muscle atrophy process occurring during catabolic states, making MuRF1 a prime candidate for pharmacological treatments against muscle wasting. Indeed, muscle wasting is an associated event of several diseases (e.g., cancer, sepsis, diabetes, renal failure, etc.) and negatively impacts the prognosis of patients, which has stimulated the search for MuRF1 inhibitory molecules. However, studies on MuRF1 cardiac functions revealed that MuRF1 is also cardioprotective, revealing a yin and yang role of MuRF1, being detrimental in skeletal muscle and beneficial in the heart. This review discusses data obtained on MuRF1, both in skeletal and cardiac muscles, over the past 20 years, regarding the structure, the regulation, the location and the different functions identified, and the first inhibitors reported, and aim to draw the picture of what is known about MuRF1. The review also discusses important MuRF1 characteristics to consider for the design of future drugs to maintain skeletal muscle mass in patients with different pathologies.

Temporomandibular Disorders Slow Down the Regeneration Process of Masticatory Muscles: Transcriptomic Analysis

“…As shown in our investigation, TRIM63 was upregulated, encoding MuRF1, a member of the ubiquitin-ligase E3 class. In various pathological conditions, when MuRF1 is overexpressed, there is an increase in proteolysis, probably of contractile proteins, which over time degenerates into muscle atrophy [ 61 ]. Interestingly, a study by Sacheck et al involves the administration of dexamethasone in myoblast cultures.…”

Ubiquitin Ligases at the Heart of Skeletal Muscle Atrophy Control

“…Upon myostatin binding, Mafbx/Atrogin-1 and genes involved in the degradation of several anabolic factors (ribosomal proteins, translation initiation factors, MyoD, desmin and vimentin) are up-regulated [ 49 , 66 ] and the AKT/mTORC1 pathway is inhibited [ 67 ]. TGF-ß signaling also regulates MuRF1/Trim63 expression through the synergistic action of FOXO3a and SMAD3 [ 68 , 69 ] (see [ 12 ] for a recent review). Similarly, Activin A ligand negatively regulates muscle mass by binding to the same receptor than myostatin and by activating the same intracellular pathway [ 70 , 71 , 72 ].…”

“…These opposites roles in both kind of muscles imply the development of skeletal muscle-specific drugs to inhibit MuRF1/TRIM63. Moreover, one should also take into account that MuRF1/TRIM63 has two homologs, MuRF2 and MuRF3 that share some redundant functions and could replace its role [ 12 ].…”

“…Within muscle atrophy, numerous ubiquitinating enzymes are now identified for their involvement in the regulation of both anabolic and catabolic pathways during the atrophy process, notably by being responsible for the degradation of the contractile proteins [ 12 ]. The E3 Ub ligases appear to be at the heart of these regulations and some of them may prove to be efficient therapeutic drug strategies with roughly two main approaches: (i) indirect modulation of an E3 ligase by targeting the signals involved in its regulation [ 13 , 14 , 15 , 16 ] or (ii) direct inhibition of the E3 ligase [ 17 , 18 , 19 ].…”

Confounding Roles of ER Stress and the Unfolded Protein Response in Skeletal Muscle Atrophy

“…The ubiquitin-proteasome system (UPS) represents one of the major proteolytic mechanism in skeletal muscle [ 7 , 8 , 9 ]. In addition to the well-known muscle-specific E3 ubiquitin ligases, muscle RING finger 1 (MuRF1 also known as TRIM63; [ 10 ]) and muscle atrophy F-box (MAFbx)/atrogin-1, several other key ligases such as neural precursor cell expressed developmentally down-regulated protein 4.1 (Nedd4.1), tumor necrosis factor receptor (TNFR)-associated factor 6 (TRAF6), and muscle ubiquitin ligase of the SCF complex in atrophy-1 (MUSA1), have been identified and mediate proteolytic degradation of both thick and thin filaments in skeletal muscle [ 4 , 11 , 12 ]. The autophagic-lysosomal pathway (ALP) is another preeminent catabolic mechanism involved in the clearance of cytoplasmic components such as defunct organelles as well as misfolded or other harmful proteins [ 13 , 14 ].…”