title: Sphingomyelinase promotes oxidant production and skeletal muscle contractile dysfunction through activation of NADPH oxidase.
abstract: Elevated concentrations of sphingomyelinase (SMase) have been detected in a variety of diseases. SMase has been shown to increase muscle derived oxidants and decrease skeletal muscle force; however, the sub-cellular site of oxidant production has not been elucidated. Using redox sensitive biosensors targeted to the mitochondria and NADPH oxidase (Nox2), we demonstrate that SMase increased Nox2-dependent ROS and had no effect on mitochondrial ROS in isolated FDB fibers. Pharmacological inhibition and genetic knockdown of Nox2 activity prevented SMase induced ROS production and provided protection against decreased force production in the diaphragm. In contrast, genetic overexpression of superoxide dismutase within the mitochondria did not prevent increased ROS production and offered no protection against decreased diaphragm function in response to SMase. Our study shows that SMase induced ROS production occurs in specific sub-cellular regions of skeletal muscle; however, the increased ROS does not completely account for the decrease in muscle function.
authors: Department of Molecular Physiology and Biophysics, Baylor College of Medicine Houston, TX, USA.
authors: James A
authors: JA
authors: Loehr
authors: Department of Molecular Physiology and Biophysics, Baylor College of Medicine Houston, TX, USA.
authors: Reem
authors: R
authors: Abo-Zahrah
authors: Department of Molecular Physiology and Biophysics, Baylor College of Medicine Houston, TX, USA.
authors: Rituraj
authors: R
authors: Pal
authors: Department of Molecular Physiology and Biophysics, Baylor College of Medicine Houston, TX, USA.
authors: George G
authors: GG
authors: Rodney
keywords: Nox2; ROS; force; skeletal muscle; sphingomyelinase
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