Muscle RING-finger 2 and 3 maintain striated-muscle structure and function.

Area of Science:

• Muscle physiology
• Protein biochemistry
• E3 ubiquitin ligases

Background:

• Muscle-specific RING-finger (MuRF) proteins are E3 ubiquitin ligases vital for muscle structure and function.
• MuRF2 and MuRF3 interact with microtubules and contribute to sarcomere formation, exhibiting functional redundancy.
• The in vivo significance of MuRF2 and MuRF3 functional redundancy in striated muscles remained unexplored.

Purpose of the Study:

• To investigate the cooperative function of MuRF2 and MuRF3 in skeletal muscle and the heart.
• To determine the in vivo importance of MuRF2 and MuRF3 functional redundancy.

Main Methods:

• Generation and phenotypic characterization of MuRF2 and MuRF3 double knockout (DKO) mice.
• Comprehensive analysis of skeletal muscle and heart using histology, electron microscopy, and molecular techniques.
• Assessment of muscle force, cardiac function, and cardiomyocyte function in vitro and in vivo.

Main Results:

• DKO mice developed protein aggregate myopathy in skeletal muscle, with reduced force production and a shift to slow-twitch fibers.
• MuRF2 and MuRF3 deficiency in the heart resulted in impaired systolic and diastolic function.
• Increased beta/slow myosin heavy chain expression and altered calcium handling were observed in DKO hearts.

Conclusions:

• The functional redundancy of MuRF2 and MuRF3 is essential for maintaining skeletal muscle and cardiac structure and function.
• MuRF proteins play a critical role in striated muscle homeostasis in vivo.