P.4.1 PIP kinases, muscle development, and the pathogenesis of myotubular myopathy

Abstract

Myotubular myopathy (MTM) is a severe congenital myopathy with no currently identified treatment. MTM is caused by mutations in MTM1, a phosphatase that dephosphorylates 3-position phosphoinositides. Through the use of vertebrate model systems, the consequences (s) of MTM1 mutation in skeletal muscle in vivo are beginning to be unraveled. In particular, work from several laboratories (including our own) has demonstrated that loss of MTM1 (1) increases the levels of PI3P in skeletal muscle and (2) results in the disruption of the structure and function of the EC coupling apparatus. Based on these data, one hypothesis to explain MTM is that pathologic elevation of PI3P results in aberrant EC coupling, which in turn causes muscle weakness and severe neurologic disability. A correlate hypothesis is that lowering PI3P levels in MTM will enable normal muscle structure and will thus ameliorate the disease. These hypotheses lead to 2 critical questions: What is the consequence of reducing PI3P levels on normal skeletal muscle development? What is the impact of reducing PI3P levels on MTM pathogenesis? The goal of this study is to address these questions by studying models with reduced PI3P. We have created knockout mice that lack either Pik3c2b or Pik3c3, the kinases responsible for PI3P production in skeletal muscle. Using these animals, we have identified unique and non-overlapping functions for these kinases, including the observation that loss of Pik3c3 results in a muscular dystrophy phenotype. Furthermore, we have tested the concept of PI3P reduction as a therapeutic strategy for MTM by crossbreeding individual kinase knockouts with Mtm1 knockouts. Preliminary data shows that reduced expression of one of the kinases significantly improves the Mtm1 phenotype. In all, our data reveals for the first time the role of 3-PI kinases in skeletal muscle, and identifies a potential therapeutic target for the treatment of MTM.