A.Z. Reznick, M. Bar-Shai

Aging humans and other mammals lose a substantial amount of their skeletal muscle mass in advanced age, a process termed "Sarcopenia of Old Age". In recent years, mounting evidence has suggested that both extracellular and intracellular degradation processes take place as a result of muscle injury or limb immobilization. These include degradation of extracellular matrix proteins by matrix metalloproteinases (MMPs), and degradation of intracellular proteins by the ubiquitin- proteasome system , lysosomal and calcium- dependent proteases. Nuclear Factor- kB (NF-kB) is a redox- sensitive transcription factor, upregulated by a wide variety of stress stimuli including oxidative stress . The role of NF-kB in disuse atrophy and sarcopenia of old age is still unclear. Methods: In Vivo, we employ the technique of External Fixation to immobilize the hindlimbs of young and old Wistar rats. In Vitro, we use the L8 rat myoblast cell line to investigate various stimuli leading to upregulation of NF-kB transcriptional activity and increased intracellular protein degradation in skeletal muscle cells. Results: In Vivo,we have shown that both MMPs extracellularly and the ubiquitin- proteasome system intracellularly are activated at the later stage of limb immobilization. So are the lysosomal proteases in the macrophages invading muscle tissue. We have also demonstrated that there is substantial difference in the kinetics and characteristics of proteolytic processes between young and old animals. In Vitro,we have shown that NF-kB is activated in muscle cells in response to the oxidation and nitration of the intacellular milieu. Interestingly, the activation of NF-kB by nitric oxide and peroxynitrite seems to be under the control of two distict pathways of signal tansduction. Conclusions: Our results demonstrate that the time scale for the activation of the intra and extracellular proteolytic systems is quite similar, indicating the existence of a possible link between the two types of systems.

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oxidative stress