Muscle weakness in Nemaline Myopathy: what is the cause and can it be treated

Problem to be solved: The mechanisms leading to muscle weakness in Nemaline Myopathy (NM) are obscure, which hampers the development of therapy. Background: NM mainly affects children; it severely weakens their diaphragm leading to suffocation. Six mutated genes have been observed in NM. Strikingly, all code for proteins of the sarcomeric thin filament, a microstructure crucial for muscle function. Whether the functioning of the thin filament is affected by the genetic defects remains to be studied in detail, and many important questions have yet to be answered. The two most pressing ones are: Hów is thin filament function affected in NM, and does this explain muscle weakness? This research program builds on recent studies, funded by my NWO-VENI grant, which suggest that the nature of muscle weakness strongly depends on which of the six genes is involved. A better understanding of such genotype-phenotype correlations is important, as it allows to develop genotype-targeted treatment strategies. Approach: I will establish how thin filament structure and function are affected in NM. I will focus on NM caused by mutations in nebulin – a major constituent of the thin filament – which represents the main form of NM. Innovation: Techniques to be used range from skinned muscle cell to whole muscle physiology and from X-ray diffraction to super-resolution microscopy. The availability of these techniques in combination with unique patient biopsies and novel knockout mouse models, positions me ideally to tackle the problem posed. To restore muscle strength, I propose -on the basis of pilot data- to test novel drugs that act as calcium sensitizers. Impact: This research program is positioned at the level of basic science and its translation towards direct clinical application; its outcome might provide an impetus to studies on muscular disorders caused by mutations in thin filament proteins in general, such as cardiomyopathies.