Mouse Genome Informatics
involves: 129S1/Sv * 129X1/SvJ * C57BL/6
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
• 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

• 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)
• other muscles in which necrotic fibers are detected, although at lower frequencies, include the 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
Bethlem Myopathy 158810 J:51410 , J:86734