Muscle Weakness and Fibrosis Due to Cell Autonomous and Non-cell Autonomous Events in Collagen VI Deficient Congenital Muscular Dystrophy

Abstract

Congenital muscular dystrophies with collagen VI deficiency are inherited muscle disorders with a broad spectrum of clinical presentation and are caused by mutations in one of COL6A1–3 genes. Muscle pathology is characterized by fiber size variation and increased interstitial fibrosis and adipogenesis. In this study, we define critical events that contribute to muscle weakness and fibrosis in a mouse model with collagen VI deficiency. The Col6a1GT/GT mice develop non-progressive weakness from younger age, accompanied by stunted muscle growth due to reduced IGF-1 signaling activity. In addition, the Col6a1GT/GT mice have high numbers of interstitial skeletal muscle mesenchymal progenitor cells, which dramatically increase with repeated myofiber necrosis/regeneration. Our results suggest that impaired neonatal muscle growth and the activation of the mesenchymal cells in skeletal muscles contribute to the pathology of collagen VI deficient muscular dystrophy, and more importantly, provide the insights on the therapeutic strategies for collagen VI deficiency.

COX6A2 variants cause a muscle‐specific cytochrome c oxidase deficiency

“…Frozen skeletal muscles were sliced and solubilized in a buffer containing 0.125M Tris, 2% sodium dodecyl sulfate (SDS), 10% glycerol, 5% 2‐mercaptoethanol, pH 6.8. SDS–polyacrylamide gel electrophoresis (PAGE) was conducted following Laemmli's method . An equal amount of proteins (25μg) was electrophoresed through 16% Tricine Protein Gels (Thermo Fisher Scientific, Waltham, MA) and transferred onto polyvinylidene difluoride (PVDF) membrane.…”

“…18 An equal amount of proteins (25μg) was electrophoresed through 16% Tricine Protein Gels (Thermo Fisher Scientific, Waltham, MA) and transferred onto polyvinylidene difluoride (PVDF) membrane. SDSpolyacrylamide gel electrophoresis (PAGE) was conducted following Laemmli's method.…”

“…SDSpolyacrylamide gel electrophoresis (PAGE) was conducted following Laemmli's method. 18 An equal amount of proteins (25μg) was electrophoresed through 16% Tricine Protein Gels (Thermo Fisher Scientific, Waltham, MA) and transferred onto polyvinylidene difluoride (PVDF) membrane. The membrane was incubated with the following antibodies (product name, dilution): anti-COX6A2 (LS-C166966, 1:1,000; LSBio, Seattle, WA), anti-TFAM (H00007019-D01, 1:1,000; Abnova, Taipei, Taiwan).…”

Glycosaminoglycan Modification of Decorin Depends on MMP14 Activity and Regulates Collagen Assembly

“…A reduction in procollagen production observed in cells of ngDCN mice may appear to be at odds with the increased muscle and AT fibrosis observed for that model. However, mutations in COL6A1 and other COL6 chain genes also result in congenital muscular dystrophies and are similarly characterized by increased interstitial fibrosis and adipogenesis [ 73 ]. A phenotype strikingly similar to that of ngDCN, both in the skin and skeletal muscle, has been observed for mouse Col6a1 mutants [ 4 , 74 , 75 ].…”

Targeted deletion of RIC8A in mouse neural precursor cells interferes with the development of the brain, eyes, and muscles

“…Histological analysis of skeletal muscles in Nes;Ric8a CKO mice revealed the disorganization and atrophy of muscle fibers and endomysial‐fibrosis‐like appearance. In the case of muscle wasting diseases, the proportion of fibrous and adipose tissue increases and these replace the lost muscle (Desguerre et al, ; Bönnemann et al, ; Noguchi et al, ). Muscle atrophy develops as a result of a failure of motor neurons to correctly innervate the muscle fiber, and due to misregulated function of trophic factors released at the synapse (Cisterna et al, ).…”