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

Abstract

Collagen VI myopathies are genetic disorders caused by mutations in collagen 6 A1, A2 and A3 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 patients with collagen VI pathology. The interactome map identified common pathways suggesting a previously undetected connection between circadian genes and collagen VI pathology. Intriguingly, Bmal1 −/− (also known as Arntl) mice, a well-characterized model displaying arrhythmic circadian rhythms, showed profound deregulation of the collagen VI pathway and of 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 might modify muscle damage pathogenesis.

Pharmacological inhibition of REV-ERB stimulates differentiation, inhibits turnover and reduces fibrosis in dystrophic muscle

“…However, whether the circadian clock is integral to the process of REV-ERB directed muscle repair is unclear. RNA seq analysis of muscle samples from patients with collagen VI myopathies have linked aberrant circadian regulation to deregulation of autophagy genes, with the effect on collagen VI regulation mirrored in Bmal1 knockout mice 61 . While the contributions of diurnal fluctuations to muscle turnover have been identified 22 , 23 , 62 it is uncertain what circadian factors contribute to DMD dystrophinopathy.…”

The circadian rhythm in intervertebral disc degeneration: an autophagy connection

“…In the heart, BMAL1 protects cardiomyocytes under hyperglycemic conditions by inducing autophagy through mTORC1 signaling downregulation 67 . BMAL1 −/− mice exhibit increased LC3A and decreased p62 levels in muscle, whereas Beclin-1 levels are unchanged 68 . AMPK activation has been indicated to be involved in the regulation of BMAL1 in autophagy 68 .…”

“…BMAL1 −/− mice exhibit increased LC3A and decreased p62 levels in muscle, whereas Beclin-1 levels are unchanged 68 . AMPK activation has been indicated to be involved in the regulation of BMAL1 in autophagy 68 . Cardiomyocyte-specific BMAL1 knockout (CBK) and cardiomyocyte-specific Clock mutant (CCM) mice exhibit hyperactivation of the PI3K Class 1/Akt/mTOR signaling axis, which likely contributes to attenuation of autophagy and the augmentation of protein synthesis 69 .…”

The physiology of movement

“…Allelic differences in clock genes like OtsClock1b and Adcyap1 are not only associated with differences in timing and distance of migration but also affect morphology, hormone production and timing of reproduction [146,148,149]. Recent work showed that migratory and nonmigratory butterflies (Danaus plexippus) differ in the Collagen IV alpha-1 gene, which participates in muscle development, metabolism and circadian rhythm pathways [150,151]. This indicates that a limited number of genes regulate multidimensional traits associated with condition-dependent migration.…”