Many previous investigations have provided correlative data suggesting that calpains play key roles in muscle cell necrosis and regeneration in muscular dystrophy and in muscle cell fusion. However, little experimental data exist to substantiate calpains' hypothetical roles in these processes. In this investigation, transgenic models will be employed to examine the individual roles that the three calpain isoforms play in normal growth and development of muscle, and in the pathological process of mdx dystrophy. This will involve the creation of transgenic mice that overexpress isoforms of calpain in a muscle-specific manner. The investigation proposed here is significant both in the new knowledge that it will contribute to our understanding of the functions of the calpain family of proteases in muscle, but also in providing information that is essential to understanding the pathophysiology of LGMD 2A (Limb Girdle Muscular Dystrophy 2A), which results from a calpain 3 mutation, and DMD (Duchenne Muscular Dystrophy), which involves increased expression and activation of calpains. The following specific aims are to be accomplished in this investigation:
Specific Aim 1. Transgenic C57 mice, that overexpress the large subunit of calpains 1, 2 or 3, will be generated to investigate the roles of calpains in normal growth and development of muscle.
Specific Aim 2. Transgenic mdx mice, that overexpress the large subunit of calpains 1, 2 or 3, will be generated to investigate the roles of calpains in muscle necrosis, regeneration and repair in muscular dystrophy.
| Guyon, Jeffrey R; Kudryashova, Elena; Potts, Alexandra et al. (2003) Calpain 3 cleaves filamin C and regulates its ability to interact with gamma- and delta-sarcoglycans. Muscle Nerve 28:472-83 |
| Spencer, M J; Guyon, J R; Sorimachi, H et al. (2002) Stable expression of calpain 3 from a muscle transgene in vivo: immature muscle in transgenic mice suggests a role for calpain 3 in muscle maturation. Proc Natl Acad Sci U S A 99:8874-9 |
| Spencer, Melissa J; Mellgren, Ronald L (2002) Overexpression of a calpastatin transgene in mdx muscle reduces dystrophic pathology. Hum Mol Genet 11:2645-55 |
