Calpain inhibition attenuates intracellular changes in muscle cells in response to extracellular inflammatory stimulation.
Idiopathic inflammatory myopathies (IIMs), comprising of polymyositis, dermatomyositis, and inclusion-body myositis, are characterized by muscle weakness and various types of inflammatory changes in muscle cells. They also show non-inflammatory changes, including perifascicular atrophy, mitochondrial changes, and amyloid protein accumulation. It is possible that some molecules/mechanisms bridge the extracellular inflammatory stimulation and intracellular non-inflammatory changes. One such mechanism, Ca(2+) influx leading to calpain activation has been proposed. In this study, we demonstrated that post-treatment with calpeptin (calpain inhibitor) attenuated intracellular changes to prevent apoptosis (Wright staining) through both mitochondrial pathway (increase in Bax:Bcl-2 ratio) and endoplasmic reticulum stress pathway (activation of caspase-12), which were induced by interferon-gamma (IFN-γ) stimulation in rat L6 myoblast cells. Our results also showed that calpeptin treatment inhibited the expression of calpain, aspartyl protease cathepsin D, and amyloid precursor protein. Thus, our results indicate that calpain inhibition plays a pivotal role in attenuating muscle cell damage from inflammatory stimulation due to IFN-γ, and this may suggest calpain as a possible therapeutic target in IIMs.
Nozaki
Kenkichi
K
Division of Neurology, Department of Neurosciences, Medical University of South Carolina, Charleston, SC 29425, USA.
Das
Arabinda
A
Ray
Swapan K
SK
Banik
Naren L
NL
D000704:Analysis of Variance; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002154:Calpain / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D002460:Cell Line; D002478:Cells, Cultured; D004151:Dipeptides / Q000494:pharmacology; D007249:Inflammation / Q000378:metabolism*; D007371:Interferon-gamma / Q000494:pharmacology; D032446:Myoblasts / Q000187:drug effects / Q000378:metabolism*; D051381:Rats
D004151:Dipeptides; C071482:calpeptin; D007371:Interferon-gamma; D002154:Calpain