MAP and kinesin-dependent nuclear positioning is required for skeletal muscle function.

Area of Science:

• Cell Biology
• Muscle Physiology
• Developmental Biology

Background:

• Skeletal muscle myofibres contain multiple nuclei, precisely positioned for optimal function.
• The molecular mechanisms governing myonuclear positioning remain largely unknown.
• Mispositioned nuclei are linked to various muscle diseases, such as centronuclear myopathies.

Purpose of the Study:

• To identify the molecular machinery responsible for myonuclear positioning in skeletal muscle.
• To investigate the physiological importance of correct nuclear positioning for muscle function.

Main Methods:

• Utilized Drosophila and cultured mammalian myotubes as model systems.
• Identified key proteins using genetic and biochemical approaches.
• Assessed the impact of protein depletion and rescue experiments on nuclear positioning and muscle function.

Main Results:

• Identified ensconsin (Ens)/microtubule-associated protein 7 (MAP7) and kinesin heavy chain (Khc)/Kif5b as essential regulators of myonuclear positioning.
• Demonstrated a physical interaction between MAP7 and Khc, with MAP7 linking Khc to microtubules.
• Showcased that impaired nuclear positioning in Drosophila mutants leads to reduced locomotion, which is rescued by restoring Ens expression.

Conclusions:

• MAP7 and Khc are evolutionarily conserved proteins critical for maintaining proper myonuclear positioning.
• Correct nuclear positioning is essential for normal muscle function.
• Defective nuclear positioning contributes to muscle dysfunction in a cell-autonomous manner.