title: Diaphragm dysfunction caused by sphingomyelinase requires the p47(phox) subunit of NADPH oxidase.
abstract: Sphingomyelinase (SMase) activity is elevated in inflammatory states and may contribute to muscle weakness in these conditions. Exogenous SMase depresses muscle force in an oxidant-dependent manner. However, the pathway stimulated by SMase that leads to muscle weakness is unclear. In non-muscle cells, SMase activates the Nox2 isoform of NADPH oxidase, which requires the p47(phox) subunit for enzyme function. We targeted p47(phox) genetically and pharmacologically (apocynin) to examine the role of NADPH oxidase on SMase-induced increase in oxidants and diaphragm weakness. SMase increased cytosolic oxidants (arbitrary units: control 203±15, SMase 276±22; P<0.05) and depressed maximal force in wild type mice (N/cm(2): control 20±1, SMase 16±0.6; P<0.05). However, p47(phox) deficient mice were protected from increased oxidants (arbitrary units: control 217±27, SMase 224±17) and loss of force elicited by SMase (N/cm(2): control 20±1, SMase 19±1). Apocynin appeared to partially prevent the decrease in force caused by SMase (n=3 mice/group). Thus, our study suggests that NADPH oxidase plays an important role on oxidant-mediated diaphragm weakness triggered by SMase. These observations provide further evidence that NADPH oxidase modulates skeletal muscle function.
authors.affiliation: Department of Applied Physiology and Kinesiology, College of Health and Human Performance, University of Florida, 1864 Stadium Rd, Rm 100FLG, Gainesville, FL 32611, United States.
authors.forename: Elaina R
authors.initials: ER
authors.lastname: Bost
authors.affiliation: Department of Applied Physiology and Kinesiology, College of Health and Human Performance, University of Florida, 1864 Stadium Rd, Rm 100FLG, Gainesville, FL 32611, United States.
authors.forename: Gregory S
authors.initials: GS
authors.lastname: Frye
authors.affiliation: Department of Applied Physiology and Kinesiology, College of Health and Human Performance, University of Florida, 1864 Stadium Rd, Rm 100FLG, Gainesville, FL 32611, United States.
authors.forename: Bumsoo
authors.initials: B
authors.lastname: Ahn
authors.affiliation: Department of Applied Physiology and Kinesiology, College of Health and Human Performance, University of Florida, 1864 Stadium Rd, Rm 100FLG, Gainesville, FL 32611, United States. Electronic address: Ferreira@hhp.ufl.edu.
authors.forename: Leonardo F
authors.initials: LF
authors.lastname: Ferreira
mesh_terms: D000818:Animals; D015153:Blotting, Western; D003964:Diaphragm / Q000378:metabolism* / Q000503:physiopathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019255:NADPH Oxidases / Q000378:metabolism*; D018384:Oxidative Stress; D013108:Sphingomyelin Phosphodiesterase / Q000378:metabolism* / Q000494:pharmacology
chemical_list: D019255:NADPH Oxidases; C060505:neutrophil cytosolic factor 1; D013108:Sphingomyelin Phosphodiesterase
keywords: Force; Sphingolipids; and Nox