Sphingomyelinase promotes oxidant production and skeletal muscle contractile dysfunction through activation of NADPH oxidase

• Main Authors: James A. Loehr, Reem eAbo-Zahrah, Rituraj ePal, George G. Rodney
• Format: Article
• Language: English
• Published: Frontiers Media S.A. 2015-01-01
• Series: Frontiers in Physiology
• Subjects: NADPH Oxidase; Reactive Oxygen Species; skeletal muscle; redox signaling; sphingomylenase
• Online Access: http://journal.frontiersin.org/Journal/10.3389/fphys.2014.00530/full

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. Pharmacological inhibition and genetic knockdown of Nox2 activity prevented SMase induced ROS production and provided protection against decreased force production. In contrast, genetic overexpression of superoxide dismutase within the mitochondria did not prevent increased ROS production and offered no protection against decreased muscle 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.