Eliminating Nox2 ROS production protects dystrophic skeletal muscle from pathological calcium influx assessed in vivo by manganese enhanced MRI

Abstract

Duchenne muscular dystrophy (DMD) is an X-linked progressive degenerative disease resulting from a mutation in the gene that encodes dystrophin, leading to decreased muscle mechanical stability and force production. Increased Nox2 ROS production and sarcolemmal Ca²⁺ influx are early indicators of disease pathology and eliminating Nox2 ROS production reduces aberrant calcium influx in young mdx mice, a model of DMD. Various imaging modalities have been used to study dystrophic muscle in vivo; however, they are based upon alterations in muscle morphology or inflammation. Manganese has been used to indirectly monitor calcium influx across the sarcolemma and may allow detection of molecular alterations in disease progression in vivo using manganese enhanced MRI (MEMRI). Therefore, we hypothesized eliminating Nox2 ROS production would decrease calcium influx in adult mdx mice and MEMRI would be able to monitor and differentiate disease status in dystrophic muscle. Both in vitro and in vivo data demonstrate eliminating Nox2 ROS protected against aberrant calcium influx and improved muscle function in dystrophic muscle. MEMRI was able to differentiate between different pathological states in vivo, with no long term effects on animal health or muscle function. We conclude that MEMRI is a viable, non-invasive technique to differentiate disease status and may provide a means to monitor and evaluate the effectiveness of potential therapies in dystrophic muscle.

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