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Combaret, L. et al.

Combaret, Béchet, Claustre, Taillandier, Richard, Attaix,

Down-regulation of genes in the lysosomal and ubiquitin-proteasome proteolytic pathways in calpain-3-deficient muscle.

Calpain-3 deficiency leads to muscular dystrophy in humans and mice and to perturbation of the NFkappaB/IkappaB pathway. As this phenotype is mainly atrophic, this study was performed to determine whether protein turnover and/or proteolytic gene expression was altered in muscles following calpain-3 deficiency. In vitro rates of protein turnover and of substrate ubiquitination, cathepsin B and B+L activities, and mRNA levels for several proteolytic genes were measured in skeletal muscles from 4-5 month-old control and calpain-3 knockout mice. Rates of protein synthesis and breakdown, cathepsin activities, and rates of substrate ubiquitination remained stable in muscles from calpain-3 deficient mice. However, and surprisingly, mRNA levels for cathepsin L, the 14-kDa ubiquitin-conjugating enzyme E2, and the C2 subunit of the 20S proteasome decreased by approximately 47% (P<0.005) in the gastrocnemius muscle from calpain-3 deficient mice. In contrast, muscle mRNA levels for ubiquitin and subunit S5a of the 26S proteasome were unaffected by calpain-3 deficiency. Taken together these data demonstrate that the expression of some genes that are involved in distinct proteolytic pathways is selectively and coordinately down-regulated without any effect on proteolysis. This suggests new pathophysiological hypotheses, e.g. a lack of maturation of NFkappaB precursor and/or a defect in specific substrate targeting.[1]

References

Down-regulation of genes in the lysosomal and ubiquitin-proteasome proteolytic pathways in calpain-3-deficient muscle. Combaret, L., Béchet, D., Claustre, A., Taillandier, D., Richard, I., Attaix, D. Int. J. Biochem. Cell Biol. (2003) [Pubmed]

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