Role of Phosphatidylinositol 3-Phosphates and Their Regulators in Skeletal Muscle Development and Disease.

[摘要] X-linked myotubular myopathy (MTM) is a severe centronuclear myopathy, characterized by profound weakness and hypotonia at birth, early mortality, and significant morbidities. MTM results from mutations in the phosphoinositide phosphatase myotubularin (MTM1), which dephosphorylates the lipid substrates phosphatidylinositol 3-phosphate (PtdIns(3)P) and phosphatidylinositol 3,5-bisphosphate (PtdIns(3,5)P2). We propose that dysregulation of PtdIns(3)P and PtdIns(3,5)P2 leads to the disease state in MTM, and that these lipids play a significant role in muscle development and homeostasis. To elucidate the effect of PtdIns(3)P dysregulation in MTM, we examined several mouse models with targeted inactivation of phosphoinositide phosphatases (Mtm1 and Fig4) and kinases (Pik3c3 and Pik3c2β). Previous studies showed that tissue-specific neuronal rescue of the spontaneously occurring Fig4 mutation of pale tremor (plt) mice prevented overt muscle weakness and the development of obvious muscle abnormalities. Our studies confirmed that the changes in skeletal muscle observed in the plt mice were primarily related to denervation. Fig4 deletion had previously been shown to rescue aspects of Mtmr2-dependent neuropathy, so we evaluated the effect of Fig4 haploinsufficiency on the myopathy of Mtm1-knockout mice. Compared with Mtm1–/Y males, mice with the genotype Fig4+/−/Mtm1–/Y displayed no improvement in muscle histology, muscle size, or longevity, indicating that reduction of FIG4 does not ameliorate the Mtm1-knockout phenotype.To further investigate the function of PtdIns(3)P in skeletal muscle, we focused on the primary kinase responsible for its production, and created a muscle-specific conditional knockout of the class III PI 3-kinase, Pik3c3. This resulted in progressive disease characterized by reduced activity and death by two months of age. Histopathology demonstrated changes consistent with a murine muscular dystrophy. Mechanistic evaluations revealed significant alterations in the autophagolysosomal pathway with mislocation of known dystrophy proteins to the lysosomal compartment. We present the first analysis of Pik3c3 in skeletal muscle, and report a novel association between deletion of Pik3c3 and muscular dystrophy.In contrast, muscle-specific deletion of Pik3c2β caused no overt physiological defects by 11 months of age, other than impaired glucose tolerance. These studies demonstrate the critical role of PIK3C3 in muscle physiology and give insight to some of the mechanisms disrupted in muscle diseases.

[发布机构] University of Michigan

[效力级别] Congenital Muscle Disease

[关键词] Phosphatidylinositol;Congenital Muscle Disease;Mouse Models;PtdIns(3)P and PtdIns(3;5)P2 Regulators in Muscle Health;Myotubular Myopathy;Science (General);Science;Neuroscience