Deep RNA profiling identified clock and molecular clock genes as pathophysiological signatures in collagen VI myopathy

Abstract

Collagen VI myopathies are genetic disorders due to mutations in collagen 6 A1, 2, and 3 genes, ranging from the severe Ullrich congenital muscular dystrophy to the milder Bethlem Myopathy, which is recapitulated by collagen VI null (Col6a1−/−) mice. Abnormalities in mitochondria and autophagic pathway have been proposed as pathogenic causes of collagen VI myopathies, but the link between collagen VI defects and these metabolic circuits remains unknown. To unravel the expression profiling perturbation in muscles with collagen VI myopathies we performed a deep RNA profiling in both Col6a1−/− mice and ColVI patients. Interactome map identified common pathways suggesting a previously undetected connection between circadian genes and collagen VI pathology. Intriguingly, Bmal1−/− mice, a well-characterized model displaying arrhythmic circadian rhythms, showed profound deregulation of the collagen VI pathway and autophagy-related genes. The involvement of circadian rhythms in collagen VI myopathies is new and links autophagy and mitochondrial abnormalities. It also opens new avenues for therapies of hereditary myopathies to modulate the molecular clock or potential gene-environment interactions that may modify muscle damage pathogenesis.