Search

Introduction: Congenital myopathies (CM) are a heterogeneous group of muscle diseases presenting at birth or early infancy, characterised by muscle weakness and specific morphological changes in the muscle biopsy. During the recent decade a growing number of genes have been discovered, however, additional novel genes are yet to be identified as genetic diagnosis cannot be currently established in many patients with congenital myopathies. Methods: Eighteen patients with CM, where mutations in suspected genes have been previously excluded, were selected for whole exome sequencing (WES). WES was carried out by deCODE genetics and the data was analysed using deCODE Clinical Sequence Miner Tool. Results: Recently, a homozygous missense mutation in exon 10 of STAC3 gene was identified in patients with Native American myopathy. Analysis of WES data in our cases identified a homozygous STAC3 mutation in a patient with King-Denborough syndrome and core-like changes on muscle biopsy. STAC3 is a muscle specific gene involved in excitation–contraction coupling process. A second patient with a severe phenotype and muscle biopsy changes suggestive of nemaline myopathy, carried a homozygous missense mutation in KLHL40. Mutations in KLHL40 have been very recently identified as a frequent cause of severe autosomal-recessive nemaline myopathy. Two heterozygous truncating TTN mutations were detected in a patient with severe cardiomyopathy and muscle biopsy suggestive of a centronuclear myopathy (CNM) supporting the emerging data that TTN mutations should be investigated as causative in cases with unresolved CNM. Conclusions: By applying WES, we were able to reveal the molecular defect in 3 out of 18 patients in whom mutations in recently described genes causing CM were identified, showing that these genes should be considered in diagnostic testing. The remaining cases carried mutations in potentially novel genes which are under investigation.

Loss of skeletal muscle mass and function occurs with increasing age. Calorie restriction (CR) increases the lifespan of C57Bl/6 mice, but not in the shorter-lived DBA/2 strain. There is some evidence that calorie restriction reduces or delays many of the age-related defects that occur in rodent skeletal muscle. We therefore investigated the effect of short (2.5 month) and longer term (8.5 and 18.5 months) CR on skeletal muscle in male and female C57Bl/6 and DBA/2 mice. We found that short-term CR increased the satellite cell number and collagen VI content of muscle, but resulted in a delayed regenerative response to injury.Consistent with this, the in vitro proliferation of satellite cells derived from these muscles was reduced by CR. The percentage of stromal cells, macrophages, hematopoietic stem cells and fibroadipogenic cells in the mononucleated cell population derived from skeletal muscle was reduced by CR at various stages. But overall, these changes are neither consistent over time, nor between strain and sex. The fact that changes induced by CR do not persist with time and the dissimilarities between the two mouse strains, combined with sex differences, urge caution in applying CR to improve skeletal muscle function across the lifespan in humans.