Striated muscle structure and function is maintained by precise control of protein synthesis and degradation; abnormalities in these processes can give rise to myopathies. The UPS degrades misfolded proteins. UPS substrate specificity is mediated by E3 ligases, such as RING-finger proteins. Muscle RING-finger (MuRF) proteins 1, 2, and 3 comprise a subfamily of the RING-finger E3 ligases that are specifically expressed in the heart and skeletal muscle. We generated Trim54/MuRF3 knockout mice and demonstrated that MuRF3 is involved in maintaining cardiac structure and function, and the integrity of the ventricular wall following acute myocardial infarction. Additionally, we found that Trim54/MuRF1–/–//Trim55/MuRF3–/– double mutant (DKO) mice display a distinct myosin storage myopathy of the heart and skeletal. Cardiac and skeletal muscles of DKO mice displayed a striking subsarcolemmal accumulation of myosin (MyHC) accompanied by cardiac hypertrophy, decreased cardiac function and reduced maximal force development of the skeletal muscle (Figure 4). MuRF1 and MuRF3 interact specifically with β/slow MyHC and MyHCIIa and utilize UbcH5a, -b, and -c as E2 ubiquitin–conjugating enzymes to catalyze the ubiquitination and degradation of these proteins. In addition, we generated and phenotypically characterized Trim55/MuRF2–/–//Trim54/MuRF3–/– DKO mice. These mice also showed a protein aggregate myopathy in the skeletal muscle with a reduction of maximal force development in the skeletal muscle. In addition, a fibre type shift towards slow/type I fibres occurred in Trim55/MuRF2–/–//Trim54/MuRF3–/– DKO soleus and extensor digitorum longus. Trim55/MuRF2–/–//Trim54/MuRF3–/– DKO hearts showed decreased systolic and diastolic function. Further analyses revealed an increased expression of the MyHC isoform β/slow and disturbed calcium handling as potential causes for the phenotype in Trim55/MuRF2–/–//Trim54/MuRF3–/– DKO hearts. Our data show that all members of the MuRF family have partially redundant functions which are important for maintenance of skeletal muscle and cardiac structure and function in vivo. We are now working on the regulation of function and activity of MuRF proteins.
