The calpains are physiologically important Ca(2+)-activated regulatory
proteases, which are divided into typical or atypical sub-families based on constituent domains. Both sub-families are present in mammals, but our understanding of
calpain function is based primarily on typical sub-family members. Here, we take advantage of the model organism Caenorhabditis elegans, which expresses only atypical calpains, to extend our knowledge of the phylogenetic evolution and function of calpains. We provide evidence that a typical human
calpain protein with a
penta EF hand, detected using custom profile hidden Markov models, is conserved in ancient metazoans and a divergent clade. These analyses also provide evidence for the lineage-specific loss of typical
calpain genes in C. elegans and Ciona, and they reveal that many
calpain-like genes lack an intact catalytic triad. Given the association between the dysregulation of typical calpains and human degenerative pathologies, we explored the phenotypes, expression profiles, and consequences of inappropriate reduction or activation of C. elegans atypical calpains. These studies show that the atypical
calpain gene, clp-1, contributes to muscle degeneration and reveal that clp-1 activity is sensitive to genetic manipulation of [Ca(2+)](i). We show that CLP-1 localizes to sarcomeric sub-structures, but is excluded from dense bodies (Z-disks). We find that the muscle degeneration observed in a C. elegans model of
dystrophin-based
muscular dystrophy can be suppressed by clp-1 inactivation and that
nemadipine-A inhibition of the EGL-19
calcium channel reveals that Ca(2+) dysfunction underlies the C. elegans MyoD model of
myopathy. Taken together, our analyses highlight the roles of
calcium dysregulation and CLP-1 in muscle
myopathies and suggest that the atypical calpains could retain conserved roles in myofilament turnover.