Tripartite motif-containing protein 63 (TRIM63) (TRIM63)

Tripartite motif-containing protein 63 (TRIM63), also known as Muscle RING-finger protein-1 (MuRF1), is a muscle-specific E3 ubiquitin ligase that plays a central role in the regulation of muscle mass [1, 13]. It is primarily expressed in skeletal and cardiac muscle, where it localizes to the Z-line and M-line of the sarcomere [3, 7]. TRIM63 is a key mediator of muscle atrophy, as it targets essential contractile proteins like myosin heavy chain (MHC) and troponins for ubiquitination and subsequent degradation by the 26S proteasome [4, 5]. Its expression is significantly upregulated during various catabolic states, including cancer cachexia, sarcopenia, and disuse atrophy, making it a high-priority therapeutic target for muscle-wasting diseases [1, 23]. In addition to its role in skeletal muscle, TRIM63 has a complex yin and yang function in the heart [1, 13]. While its absence or inhibition can prevent skeletal muscle loss, it is also involved in maintaining cardiac protein homeostasis; mutations in TRIM63 are associated with hypertrophic cardiomyopathy (HCM) [2, 10]. Consequently, therapeutic strategies focusing on TRIM63 inhibition must carefully balance the preservation of skeletal muscle with potential adverse effects on cardiac health [1, 21]. Several small-molecule inhibitors, such as P013222 and MyoMed-205, are currently under investigation in preclinical models to treat muscle wasting and cardiac cachexia [19, 21].

Other names

MuRF1Muscle RING-finger protein-1RNF28SMRZIRFMuscle-specific RING finger protein 1Striated muscle RING zinc finger protein

Inhibition of E3 ubiquitin ligase activity and disruption of the MuRF1-titin interaction to prevent the ubiquitination and subsequent proteasomal degradation of sarcomeric proteins.