Muscle Ring Fingers MuRFs comprising TRIM
Muscle Ring Fingers (MuRFs) comprising TRIM63 (MuRF1), TRIM55 (MuRF2) and TRIM54 (MuRF3) are the most studied TRIMs in the heart. However, with increasing knowledge of E3 ligases and recent advancements in the field, many other TRIMs such as TRIM8, TRIM21, TRIM24, TRIM32, TRIM45, TRIM69 and TRIM72 were found to play essential roles in cardiac function and disease pathways as discussed below and diagrammatically represented in Fig. 4.
MuRFs MuRF1, MuRF2, and MuRF3 have critical roles in skeletal and cardiac muscle. MuRF2 is found to be expressed at early onset of mouse cardiac differentiation, specifically at embryonic day 8.5 and thus is a sensitive marker for differentiating myocardium. In contrast, MuRF1 displays a strong upregulation postnatally, whereas, MuRF3 is expressed significantly only after birth . They characteristically lack B-box 1 and only have a COS domain at their carboxyl terminus. Nevertheless, MuRF1, 2, and 3 carries highly conserved RING domain at N-terminus and can form heterodimers by shared coiled-coil domains . Heterodimerization of MuRFs is possibly responsible for their multiple cellular localization and has been proposed to link titin filament and microtubule-dependent signal transduction pathways in striated muscles . Genetic mouse models of loss- or gain-of-function of MuRFs have provided deep insights into their cardiac roles. Cardiac-specific overexpression of MuRF1 led to thinning of left ventricular walls, worsened cardiac function, and heart failure upon TAC . MuRF1 has also been reported to regulate cardiac reactive oxygen species (ROS) production in mitochondria, revealing an additional cardio-protective role in ischemia reperfusion injury . Furthermore, MuRF1 inhibits cardiac fatty Cy5 EGFP mRNA oxidation by specifically inhibiting its nuclear localization, suggesting a possible role in cardiac metabolism and pathophysiology . MuRF1 and MuRF2, two closely related family members, redundantly share functional similarities and can heterodimerize . Their functional similarity extends to a degree that presence of either MuRF1 or MuRF2 is sufficient for normal cardiac function and regulation of developmental physiological hypertrophy by modulating the expression and localization of E2F transcription factors . Simultaneous absence of both proteins however results in spontaneous development of skeletal and cardiac hypertrophy . MuRF2 labeled microtubules study in cardiac sarcomeres have demonstrated its vital contribution as a transient adaptor between microtubules, titin and nascent myosin filaments, thereby playing a significant role in signaling from sarcomere to nucleus . Also, rare variants of both MuRF1 & MuRF2 were found to be associated with human hypertrophic cardiomyopathy . MuRF1 and MuRF3 in cooperation with the E2 ubiquitin-conjugating enzymes UbcH5a, -b, and -c were found to mediate degradation of myosin heavy chain β/slow (MHC β/slow) and MHC IIa via UPS, both, in vitro and in vivo . Mice lacking both MuRF1 and MuRF3 developed skeletal muscle myopathy and hypertrophic cardiomyopathy with sub-sarcolemmal MHC accumulation, myofibril fragmentation and diminished muscle performance, leading to myosin storage myopathy . These findings identify MuRF1 and MuRF3 as key E3 ubiquitin ligases for UPS-dependent turnover of sarcomeric proteins and reveal a potential molecular basis for myosin storage myopathies. MuRF2 and MuRF3 are also known to have considerable functional overlap in binding to microtubules and in sarcomere formation in the process of adaptation of striated muscle cells . Double knockout of MuRF1 and 3 in mice resulted in protein aggregate-associated myopathy in striated muscles . Moreover, hearts from this mouse line displayed reduced systolic and diastolic function, increased expression of the MHC-β/slow, and calcium handling defects in the sarcomere. Interestingly, MuRF2 and MuRF3 reportedly protect heart against diabetic cardiomyopathy via non-proteasomal modification of peroxisome proliferator activating receptors (PPAR)-α/γ transcription factors, suggesting a pivotal role in metabolic pathways as well , .