Murine Fig4 is dispensable for muscle development but required for muscle function

Area of Science:

• Cellular Biology
• Neuroscience
• Muscle Physiology

Background:

• Phosphatidylinositol phosphates (PIPs) regulate cellular processes like membrane traffic.
• Mutations in PIP-regulating enzymes cause muscle diseases, such as myotubular myopathy (MTM).
• FIG4, a PIP phosphatase, is linked to neurodegeneration; its role in skeletal muscle is unknown.

Purpose of the Study:

• To investigate the impact of FIG4 loss-of-function on skeletal muscle development and function.
• To determine if FIG4 deficiency affects excitation-contraction coupling in skeletal muscle.
• To assess if FIG4 reduction can ameliorate MTM phenotypes.

Main Methods:

• Utilized the pale tremor (plt) mouse mutant with a loss-of-function mutation in Fig4.
• Characterized skeletal muscle size, force generation, and ultrastructure in plt mice.
• Performed conditional rescue experiments in neurons and evaluated compound mutant mice (Fig4+/-/Mtm1-/Y).

Main Results:

• plt mice exhibited reduced muscle size, specific force, ultrastructural abnormalities, and increased cell death.
• No impairment in excitation-contraction coupling was observed.
• Conditional neuronal rescue prevented muscle weakness, indicating denervation as the cause of muscle abnormalities.
• FIG4 reduction did not improve the myopathy in Mtm1-knockout mice.

Conclusions:

• Loss of FIG4 leads to impaired skeletal muscle function.
• Skeletal muscle structural development is not significantly affected by FIG4 loss.
• Muscle abnormalities in FIG4-deficient mice are primarily due to denervation.