Neutral sphingomyelinase-3 mediates TNF-stimulated oxidant activity in skeletal muscle.
Neutral sphingomyelinase-3 mediates TNF-stimulated oxidant activity in skeletal muscle.
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DOI：
10.1016/j.redox.2014.07.006
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发表时间：
2014
期刊：
影响因子：
11.4
通讯作者：
Reid, Michael B.
中科院分区：
文献类型：
--
作者：
Moylan, Jennifer S.;Smith, Jeffrey D.;Horrell, Erin M. Wolf;McLean, Julie B.;Deevska, Gergana M.;Bonnell, Mark R.;Nikolova-Karakashian, Mariana N.;Reid, Michael B.
关键词：
Sphingolipid and oxidant signaling affect glucose uptake, atrophy, and force production of skeletal muscle similarly and both are stimulated by tumor necrosis factor (TNF), suggesting a connection between systems. Sphingolipid signaling is initiated by neutral sphingomyelinase (nSMase), a family of agonist-activated effector enzymes. Northern blot analyses suggest that nSMase3 may be a striated muscle-specific nSMase. The present study tested the hypothesis that nSMase3 protein is expressed in skeletal muscle and functions to regulate TNF-stimulated oxidant production. We demonstrate constitutive nSMase activity in skeletal muscles of healthy mice and humans and in differentiated C2C12 myotubes. nSMase3 (Smpd4 gene) mRNA is highly expressed in muscle. An nSMase3 protein doublet (88 and 85 kD) is derived from alternative mRNA splicing of exon 11. The proteins partition differently. The full-length 88 kD isoform (nSMase3a) fractionates with membrane proteins that are resistant to detergent extraction; the 85 kD isoform lacking exon 11 (nSMase3b) is more readily extracted and fractionates with detergent soluble membrane proteins; neither variant is detected in the cytosol. By immunofluorescence microscopy, nSMase3 resides in both internal and sarcolemmal membranes. Finally, myotube nSMase activity and cytosolic oxidant activity are stimulated by TNF. Both if these responses are inhibited by nSMase3 knockdown. These findings identify nSMase3 as an intermediate that links TNF receptor activation, sphingolipid signaling, and skeletal muscle oxidant production. Our data show that nSMase3 acts as a signaling nSMase in skeletal muscle that is essential for TNF-stimulated oxidant activity. First measures of endogenous nSMase3 protein in muscle. Detection of nSMase3 splice variant proteins. Identification of a functional role for nSMase3 in redox signaling. Identification of an intermediate in TNF/redox signaling.
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