# Lack of myotubularin phosphatase activity is the main cause of X-linked myotubular myopathy

## TL;DR

This study shows that the loss of myotubularin's phosphatase activity causes severe muscle disease in mice, highlighting its essential role in muscle health.

## Contribution

The study demonstrates that MTM1 phosphatase activity is crucial for muscle maintenance and XLMTM pathogenesis.

## Key findings

- Phosphatase-dead Mtm1 mice showed severe muscle weakness and hypotrophy.
- Elevated PI(3)P levels and disrupted mTOR/autophagy pathways were observed in mutant mice.
- Abnormal myofiber organization correlated with impaired muscle force production.

## Abstract

The MTM1 gene encodes myotubularin (MTM1), a phosphatidylinositol 3-phosphate [PI(3)P] lipid phosphatase. Loss-of-function mutations in MTM1 cause X-linked myotubular myopathy (XLMTM), a severe congenital myopathy with no available cure and a poorly understood pathomechanism. The importance of MTM1 enzymatic activity and its PI(3)P substrate in physiology under normal conditions and in XLMTM is unclear. We generated the Mtm1-KI C375S mice in which the endogenous MTM1 was converted to a phosphatase-dead protein. Mutant mice survived a median of 12 weeks and demonstrated progressively impaired motor skills. Observed muscle hypotrophy and reduced force production compared with their WT littermates (~3.9-fold reduction in absolute maximal force) were responsible for these severe phenotypes. A significantly higher level of PI(3)P was found in the muscle of Mtm1-KI C375S mice. Muscle histology and molecular characterization revealed XLMTM hallmarks, with (a) alteration of the mTOR and autophagy pathways correlating with muscle hypotrophy and (b) abnormal myofiber intracellular organization correlating with impaired muscle force. Overall, this study reveals the importance of MTM1 phosphatase activity and related PI(3)P substrate for postnatal muscle maintenance, and it highlights the significance of MTM1 phosphatase activity in the development of X-linked myotubular myopathy.

Mice with phosphatase-dead myotubularin develop severe myopathy, emphasizing the critical importance of the protein’s enzymatic activity in sustaining healthy muscle structure and function.