Myopathy phenotype of transgenic mice expressing active site-mutated inactive p94 skeletal muscle-specific calpain, the gene product responsible for limb girdle muscular dystrophy type 2A

A defect of the gene for p94 (calpain 3), a skeletal muscle-specific calpai n, is responsible for limb girdle muscular dystrophy type 2A (LGMD2A), or ' calpainopathy', which is an autosomal recessive and progressive neuromuscul ar disorder. To study the relationships between the physiological functions of p94 and the etiology of LGMD2A, we created transgenic mice that express an inactive mutant of p94, in which the active site Cys129 is replaced by Ser (p94:C129S). Three lines of transgenic mice expressing p94:C129S mRNA a t various levels showed significantly decreased grip strength. Sections of soleus and extensor digitorum longus (EDL) muscles of the aged transgenic m ice showed increased numbers of lobulated and split fibers, respectively, w hich are often observed in limb girdle muscular dystrophy muscles. Centrall y placed nuclei were also frequently found in the EDL muscle of the transge nic mice, whereas wild-type mice of the same age had almost none. There was more p94 protein produced in aged transgenic mice muscles and it showed si gnificantly less autolytic degradation activity than that of wild-type mice . Although no necrotic-regenerative fibers were observed, the age and p94:C 129S expression dependence of the phenotypes strongly suggest that accumula tion of p94:C129S protein causes these myopathy phenotypes. The p94:C129S t ransgenic mice could provide us with crucial information on the molecular m echanism of LGMD2A.