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Background  Phosphatidylinositol phosphates (PIPs) are low-abundance phospholipids that participate in a range of cellular processes, including cell migration and membrane traffic. PIP levels and subcellular distribution are regulated by a series of lipid kinases and phosphatases. In skeletal muscle, PIPs and their enzymatic regulators serve critically important functions exemplified by mutations of the PIP phosphatase  MTM1  in myotubular myopathy (MTM), a severe muscle disease characterized by impaired muscle structure and abnormal excitation–contraction coupling. FIG4 functions as a PIP phosphatase that participates in both the synthesis and breakdown of phosphatidylinositol 3,5-bisphosphate (PI(3,5)P 2 ). Mutation of  FIG4  results in a severe neurodegenerative disorder in mice and a progressive peripheral polyneuropathy in humans. The effect of  FIG4  mutation on skeletal muscle has yet to be examined.    Methods  Herein we characterize the impact of FIG4 on skeletal muscle development and function using the spontaneously occurring mouse mutant pale tremor ( plt ), a mouse line with a loss of function mutation in  Fig4 .    Results  In  plt  mice, we characterized abnormalities in skeletal muscle, including reduced muscle size and specific force generation. We also uncovered ultrastructural abnormalities and increased programmed cell death. Conversely, we detected no structural or functional abnormalities to suggest impairment of excitation–contraction coupling, a process previously shown to be influenced by PI(3,5)P 2  levels. Conditional rescue of  Fig4  mutation in neurons prevented overt muscle weakness and the development of obvious muscle abnormalities, suggesting that the changes observed in the  plt  mice were primarily related to denervation of skeletal muscle. On the basis of the ability of reduced FIG4 levels to rescue aspects of Mtmr2-dependent neuropathy, we evaluated the effect of  Fig4  haploinsufficiency on the myopathy of  Mtm1 -knockout mice. Male mice with a compound  Fig4  +/− / Mtm1  –/Y  genotype displayed no improvements in muscle histology, muscle size or overall survival, indicating that FIG4 reduction does not ameliorate the  Mtm1 -knockout phenotype.    Conclusions  Overall, these data indicate that loss of  Fig4  impairs skeletal muscle function but does not significantly affect its structural development.

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