Identification of cathepsin L as a differentially expressed message associated with skeletal muscle wasting

Alteration of skeletal muscle protein breakdown is a hallmark of a set of p athologies, including sepsis, with negative consequences for recovery. The aim of the present study was to search for muscle markers associated with p rotein loss, which could help in predicting and understanding pathological wasting. With the use of differential display reverse transcription-PCR, we screened differentially expressed genes in muscle from septic rats in a lo nglasting catabolic state. One clone was isolated, confirmed as being overe xpressed in septic skeletal muscle and identified as encoding the lysosomal cysteine endopeptidase cathepsin L. Northern- and Western-blot analysis of cathepsin L in gastrocnemius or tibialis anterior muscles of septic rats c onfirmed an elevation (up to 3-fold) of both mRNA and protein levels as ear ly as 2 days post-infection, and a further increase 6 days postinfection (u p to 13-fold). At the same time, the increase in mRNAs encoding other lysos omal endopeptidases or components of the ubiquitin-proteasome pathway did n ot exceed 4-fold. Cathepsin L mRNA was also increased in tibialis anterior muscle of rats treated with the glucocorticoid. analogue, dexamethasone, or rats bearing the Yoshida Sarcoma. The increase in cathepsin L mRNA was red uced by 40% when the tumour-bearing animals were treated with pentoxifyllin e, an inhibitor of tumour necrosis factor-alpha production. In conclusion, these results demonstrate a positive and direct correlation between catheps in L mRNA and protein level and the intensity of proteolysis, and identify cathepsin L as an appropriate early marker of muscle wasting. Cathepsin L p resumably participates in the pathological response leading to muscle loss, with glucocorticoids and tumour necrosis factor-alpha potentially being in volved in the up-regulation of cathepsin L.