Deficiency of p47phox subunit of NADPH oxidase protects skeletal muscle from depression of force stimulated by sphingomyelinase

Abstract

Chronic diseases (e.g., heart failure) increase sphingomyelinase (SMase) activity in the serum and skeletal muscle. SMase forms ceramide, which activates reactive oxygen species production by mitochondria and NADPH oxidase. Reactive oxygen species contribute to depression of force stimulated by SMase. p47phox is a subunit required for activation of NOX2 isoform of NADPH oxidase. We hypothesized that mice lacking p47phox would be protected from depression of force when treated with SMase. We exposed diaphragm bundles from genetic controls (C57BL/6J; n = 16) and p47phox knockout mice (C57BL/6J; n = 11) to vehicle (glycerol) or SMase (0.5 U/ml). Maximal tetanic force decreased in genetic controls (in N/cm2: Vehicle 20 ± 0.6, SMase 16 ± 0.7, P < 0.05), but was unchanged in p47phox knockout (in N/cm2: Vehicle 20 ± 1.0, SMase 19 ± 1.1). Our results suggest that SMase‐induced depression of force requires signaling through the p47phox subunit of NADPH oxidase. It appears that SMase increases reactive oxygen species production by NADPH oxidase, which leads to depression of force.Funding support: NIH 1K99HL098453‐01, 4R00HL098453‐02