Whole transcriptome expression profiling in collagen VI myopathies KO mice reveals muscle-specific fingerprints and arises the role of circadian clock genes as myopathy biomarkers

Collagen VI is an extracellular matix protein that forms a microfilamentous network in skeletal muscles and other organs. In humans, mutations in the collagen VI alpha1, 2 and 3 genes cause congenital muscular dystrophies as Bethlem , Ullrich and Myosclerosis. Mitochondrial pore abnormalities and defect in the autophagic pathways have been identified both in patients and in Col6a2KO mouse model. In order to bridging these findings to the transcriptome, we have performed whole expression profile in both wild type and KO mice. The transcritpomic data were also analysed by an ad hoc designed software enabling us to design an interactome map of the de-regulated transcripts highlighted by the array studies. The mice muscles analysed were diaphragm, gastrocnemious and tibilias. Various transcripts belonging to the muscle development and regeneration, also including genes involved in the apoptosis and autophagy control are consistently de-regulated in KO mice, supporting the role that these processes play in the disease pathogenesis. Interestingly, six genes acting within the circadian clock mechanisms are constantly down-regulated in KO mice. This behavior is constant in all muscles analysed, though more prominent in tibialis. The pathway scan analysis revealed connections between clock genes and apoptosis and autophagy as well as with muscle regeneration and muscle signaling, opening a previously undisclosed role of circadian rhythm in muscle diseases. These finding make clock genes down-regulation exploratory biomarkers of collagen VI pathology.