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Vol. 20, Issue 1, 509-520, January 1, 2009

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Antioxidant Levels Represent a Major Determinant in the Regenerative Capacity of Muscle Stem Cells

Kenneth L. Urish^*,, Joseph B. Vella^,, Masaho Okada, Bridget M. Deasy^,,||, Kimimasa Tobita^¶, Bradley B. Keller^¶, Baohong Cao, Jon D. Piganelli^¶, and Johnny Huard^,,||,#

*Department of Orthopaedics and Rehabilitation, and Department of Surgery, Penn State Milton S. Hershey Medical Center, Hershey, PA, 17033; Departments of Bioengineering, ^||Orthopaedic Surgery, and ^#Molecular Genetics and Biochemistry, University of Pittsburgh, Pittsburgh, PA, 15260; and Stem Cell Research Center, Rangos Research Center and ^¶Department of Pediatrics, Children's Hospital of Pittsburgh, PA 15213

Submitted March 14, 2008; Revised October 20, 2008; Accepted October 31, 2008
Monitoring Editor: J. Silvio Gutkind

Stem cells are classically defined by their multipotent, long-term proliferation, and self-renewal capabilities. Here, we show that increased antioxidant capacity represents an additional functional characteristic of muscle-derived stem cells (MDSCs). Seeking to understand the superior regenerative capacity of MDSCs compared with myoblasts in cardiac and skeletal muscle transplantation, our group hypothesized that survival of the oxidative and inflammatory stress inherent to transplantation may play an important role. Evidence of increased enzymatic and nonenzymatic antioxidant capacity of MDSCs were observed in terms of higher levels of superoxide dismutase and glutathione, which appears to confer a differentiation and survival advantage. Further when glutathione levels of the MDSCs are lowered to that of myoblasts, the transplantation advantage of MDSCs over myoblasts is lost when transplanted into both skeletal and cardiac muscles. These findings elucidate an important cause for the superior regenerative capacity of MDSCs, and provide functional evidence for the emerging role of antioxidant capacity as a critical property for MDSC survival post-transplantation.

Address correspondence to: Johnny Huard (jhuard{at}pitt.edu)

Abbreviations used: DEM, diethyl maleate; EDA, end-diastolic area; EDD, end-diastolic dimension; ESD, end-systolic dimension; MHC, skeletal fast myosin heavy chain; FAC, fractional area change; FS, fractional shortening; GSH, glutathione; MCB, monochlorobimane; MDSC, muscle-derived stem cell; NF-B, nuclear factor kappa B; ROS, reactive oxygen species; SOD, superoxide dismutase.