Intracellular redox potential of skeletal muscle becomes progressively more oxidized with aging, negatively impacting regenerative ability. We examined the effects of oxidizing redox potential on terminal differentiation of cultured C2C12 myoblasts. Redox potentials were manipulated by changing the culture O 2 environment, by free radical scavenging, or addition of H 2 O 2. Intracellular reactive oxygen species (ROS) production was higher in 20% environmental O 2 and in this condition, redox potential became progressively oxidized compared to cultures in 6% O 2. Treatment with a ROS trapping agent (phenyl-N-tert-butylnitrone, PBN) caused reducing redox potentials and enhanced C2C12 differentiation, while addition of 25 μM H 2 O 2 to cells in 20% O 2 dramatically slowed differentiation. Under these most oxidative conditions, quantitative PCR showed a significant decrease in myogenic basic helix-loop-helix transcription factor expression compared to cultures treated with phenyl PBN or grown in 6% O 2 . Thus, oxidative intracellular environments impair myoblast differentiation, while reducing environments favor myogenesis.

These studies suggest that stem or progenitor cell-mediated therapies may be useful for the treatment of pain after nerve injury, and deserve further study to elucidate the mechanisms of analgesia.

The purpose of this study was to explore the role of endothelin in neuropathic pain. Endothelins (ET) are a family (ET-1, ET-2, ET-3) of ubiquitously expressed peptides involved in control of vascular tone. Injected ET-1 causes intense pain via activation of ETA receptors, modulated by analgesic signals initiated by ETB receptor activation. Using a rat model of chronic constriction injury of the sciatic nerve, we found that pharmacologic ETA receptor antagonism acutely and significantly reduced thermal and mechanical hyperalgesic responses 5 days after injury. Furthermore, ET-1 and the ETA receptor are locally upregulated at the site of chronic constriction injury at both the message and the protein levels, suggesting that ET-1 may be involved in establishing pain after the injury. These data point to ET-1 as an important mediator of pain in general and suggest that ETA antagonism deserves study as a potential novel therapy for neuropathic pain.

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