The Role of Cysteine Cathepsins in Suppressing the Peroxisome Proliferator-Activated Receptor R (Pparr) Co-Activator 1a (Pgc-1a) Expression in the Process of Skeletal Muscle Atrophy and Development of Preclinical Therapeutics Model

Project: A - Government Institutionb - Ministry of Science and Technology

Description

Muscle atrophy is the leading cause of disability after peripheral nerve trauma (PNT). Annual incidence is approximately 45 cases per 100000, similar to the incidence of epilepsy. For the long-term effects in skeletal muscle atrophy after PNT, the process is irreversible. The quality of life and social health impact will be affected for these miserable outcome after PNT, not only for adult but also for the young infant. Transcriptional coactivator peroxisome proliferator-activated receptor γ coactivator-1 α (PGC-1α) as an important regulator of mitochondrial biogenesis. Most of the PGC-1α in resting skeletal muscle is in the cytosol. Activation of PGC-1α may mediate the initial phase of the exercise-induced adaptive increase in muscle mitochondria, whereas the subsequent increase in PGC-1α protein sustains and enhances the increase in mitochondrial biogenesis. Cathepsins, comprising the catalytic classes of serine, aspirate and cysteine peptidases, are involved in normal physiological processes, including angiogenesis and vasculogenesis. Cysteine cathepsins are involved in cell apoptosis and autophagy, in tumor angiogenesis, in degradation of extracellular matrix, facilitating growth, invasion, and metastasis of tumor cells, and in events of inflammatory and immune responses. Cathepsin L, one of the cysteine cathepsins, localizes primary to lysosomes, also found in the cell nucleus and extracellularly. It plays the important roles in cell differentiation and proliferation, skin homeostasis and antigen presentation. In the present study, we hypothesize that (1) how interactions between cathepsin and PGC-1α families during skeletal muscle atrophy? (2) do cathepsin inhibitors/PGC-1α activators resist skeletal muscle atrophy? (3) what are the major underlying mechanisms involved in the skeletal muscle atrophy without nerve stimulation? Based on our preliminary data, the results showed the elevation in cathepsin L mRNA and decreased the expression of PGC-1α mRNA in the mouse hindlimb muscle after sciatica axotomy. The relationships between cathepsin L and PGC-1α are necessary to be clarified. Furthermore, our preliminary findings showed the evidence that cathepsin L interacted directly with PGC-1. Thus, the specific cathepsin inhibitors and PGC-1 activators would be the negative and positive control for examining our hypothesis in the next step. Therefore, we would like to provide in vivo and in vitro experimental studies to explore the possible mechanisms via the denervated animal and patients-derived skeletal muscle tissue and cell lines. These would be advantages for disease modeling and therapeutics screening. The overall findings would provide the cascade mechanisms involved in the skeletal muscle atrophy caused by nerve damage, and by using the in vitro and in vivo models, we would successfully select potent candidates for pre-clinical treatments or complementary therapy.
StatusFinished
Effective start/end date8/1/167/31/17