Phenotypes Associated with This Genotype

Genotype
MGI:3037904

• Allelic Composition: Col6a1^tm1Gmb/Col6a1^tm1Gmb
• Genetic Background: involves: 129S1/Sv * 129X1/SvJ * C57BL/6

• ♀: phenotype observed in females
• ♂: phenotype observed in males
• N: normal phenotype

muscle

muscle phenotype ( J:51410 )

N • the observed myopathy does not impair the performance of the muscular system significantly up to 1 year of age

N • in addition, the serum levels of creatine kinase remain unaffected in homozygous mutant mice

abnormal muscle morphology ( 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%)

abnormal skeletal muscle morphology ( J:86734 )

• 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

abnormal diaphragm morphology ( J:51410 )

• the highest frequency of altered fibers is noted in the diaphragm (up to 20% of fibers are hypercontracted or necrotic in homozygous mutant mice)

abnormal intercostal muscle morphology ( J:51410 )

• necrotic fibers are detected

skeletal muscle necrosis ( J:51410 )

• 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

impaired skeletal muscle contractility ( J:86734 )

• 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

myopathy ( J:51410 )

• 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		DO ID	OMIM ID(s)	Ref(s)
Bethlem myopathy		DOID:0050663	OMIM:158810	J:51410 , J:86734