Mouse Genome Informatics
hm
    Col6a1tm1Gmb/Col6a1tm1Gmb
involves: 129S1/Sv * 129X1/SvJ * C57BL/6
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
       
muscle
N
• the observed myopathy does not impair the performance of the muscular system significantly up to 1 year of age (J:51410)
• in addition, the serum levels of creatine kinase remain unaffected in homozygous mutant mice (J:51410)
• homozygous mutant mice display a significant increase in the central nuclei, indicating muscle fiber regeneration; at some sites, the percentage of central nuclei is very high (>50%)
• electron micrographs of diaphragm and FDB transverse sections revealed mitochondria with abnormal cristae of a tubular shape, and abnormal matrix density associated with the presence of dense bodies in approximately 30% of mutant fibers
• sarcomeres, sarcolemma and basal lamina appear normal, despite significant dilations in SR at the level of triadic system
• fibers with organelle alterations exhibit peripheral chromatin condensation and an irregular shape, indicating significant apoptosis in mutant myonuclei
• upon incubation with oligomycin, an inhibitor of mitochondrial F1FO-ATP synthase, mutant fibers display an abnormally fast mitochondrial depolarization, Ca2+ deregulation and elevated apoptosis (approximately 7-fold relative to wild-type); these defects can be normalized by plating mutant myofibers on collagen VI or by addition of cyclosporin A, the inhibitor of mitochondrial permeability transition pore
• notably, treatment of homozygous mutant mice with cyclosporin A restores the muscle ultrastructural abnormalities and significantly diminishes the number of apoptotic nuclei in vivo
• the highest frequency of altered fibers is noted in the diaphragm (up to 20% of fibers are hypercontracted or necrotic in homozygous mutant mice)
• necrotic fibers are detected
• muscle necrosis is present at all ages examined (3, 10, 20 and 40 days and 4 and 5 months after Evan's blue dye injection) in homozygous mutant mice
• muscles in which necrotic fibers are detected include the diaphragm, intercostal muscle, as well as the external oblique and straight abdominal muscles, and the femoral medial large muscle
• loss of contractile strength is observed predominantly in the diaphragm, but is also detected in flexor digitorum brevis (FDB) and other hindlimb muscles
• in homozygous mutant diaphragm strips, isometric tetanic tension is significantly decreased; twitch tension is even more reduced and relaxation time is prolonged
• reduced contractile strength is confirmed by mechanical measurements on single skinned fibers isolated from the mutant diaphragm and gastrocnemius during maximal Ca2+ activation; about one-third of the skinned fibers display structural changes and shape irregularities
• skeletal muscles of homozygous mutant mice display signs of myopathy, including muscle necrosis and phagocytosis, and a significant variation in fiber diameter
• injection of Evan's blue dye revealed the presence of hypercontracted or necrotic fibers
• alterations in muscle fibers have an early onset and a limited or absent progression and their pattern of distribution is independent of muscle type

Mouse Models of Human Disease
OMIM IDRef(s)
Bethlem Myopathy 158810 J:51410 , J:86734