Correlation Engine 2.0
Clear Search sequence regions


  • bapta am (1)
  • calcium (2)
  • calpain (14)
  • cell (4)
  • cytokines (1)
  • diaphragm (6)
  • gw4869 (6)
  • IFN γ (1)
  • IL 1β (1)
  • mice (4)
  • nSMase2 (4)
  • nSMase3 (2)
  • patients (1)
  • proteolysis (1)
  • sepsis (1)
  • skeletal muscle (4)
  • Smpd3 (1)
  • sphingomyelin (2)
  • therapies (1)
  • TNF α (1)
  • vitro (1)
  • Sizes of these terms reflect their relevance to your search.

    Calpain contributes to infection-induced diaphragm dysfunction but the upstream mechanism(s) responsible for calpain activation are poorly understood. It is known, however, that cytokines activate neutral sphingomyelinase (nSMase) and nSMase has downstream effects with the potential to increase calpain activity. We tested the hypothesis that infection-induced skeletal muscle calpain activation is a consequence of nSMase activation. We administered cytomix (20 ng/ml TNF-α, 50 U/ml IL-1β, 100 U/ml IFN-γ, 10 μg/ml LPS) to C2C12 muscle cells to simulate the effects of infection in vitro and studied mice undergoing cecal ligation puncture (CLP) as an in vivo model of infection. In cell studies, we assessed sphingomyelinase activity, subcellular calcium levels, and calpain activity and determined the effects of inhibiting sphingomyelinase using chemical (GW4869) and genetic (siRNA to nSMase2 and nSMase3) techniques. We assessed diaphragm force and calpain activity and utilized GW4869 to inhibit sphingomyelinase in mice. Cytomix increased cytosolic and mitochondrial calcium levels in C2C12 cells (P < 0.001); addition of GW4869 blocked these increases (P < 0.001). Cytomix also activated calpain, increasing calpain activity (P < 0.02), and the calpain-mediated cleavage of procaspase 12 (P < 0.001). Procaspase 12 cleavage was attenuated by either GW4869 (P < 0.001), BAPTA-AM (P < 0.001), or siRNA to nSMase2 (P < 0.001) but was unaffected by siRNA to nSMase3. GW4869 prevented CLP-induced diaphragm calpain activation and diaphragm weakness in mice. These data suggest that nSMase2 activation is required for the development of infection-induced diaphragm calpain activation and muscle weakness. As a consequence, therapies that inhibit nSMase2 in patients may prevent infection-induced skeletal muscle dysfunction. Copyright © 2015 the American Physiological Society.

    Citation

    Gerald S Supinski, Alexander P Alimov, Lin Wang, Xiao-Hong Song, Leigh A Callahan. Neutral sphingomyelinase 2 is required for cytokine-induced skeletal muscle calpain activation. American journal of physiology. Lung cellular and molecular physiology. 2015 Sep 15;309(6):L614-24

    Expand section icon Mesh Tags

    Expand section icon Substances


    PMID: 26138644

    View Full Text