Cigarette smoke effects on nitric oxide-dependent muscle regeneration
Abstracts
Initial Award Abstract |
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It is well established that the persistent use of tobacco cigarettes has a profound impact on exercise tolerance. This ultimately reduces mobility and quality of life for those who develop chronic obstructive pulmonary disease (COPD). Loss of muscle mass is a main factor in impaired exercise tolerance and results from both atrophy and inefficient regenerative capacity of the peripheral muscles. Tobacco smokers show a high incidence of muscle injuries and slow recovery. However, alterations in muscle regenerative mechanisms in smokers and COPD patients, in particular are poorly investigated. Muscle repair is initiated by the intracellular production of the free radical nitric oxide (NO) which activates muscle stem cells, also known as satellite cells present around muscle fibers (myofibers). The activation of satellite cells leads to myofiber repair. Although the many harmful components of cigarette smoke are considered pro-oxidants, skeletal muscles obtained from smokers show less capacity to produce NO. Our laboratory has shown that mice exposed to cigarette smoke have less muscle mass, altered muscle contractile function, fewer and less active satellite cells around myofibers, and lower amounts of NO synthases (enzyme that produces NO) in muscles than in non-smoking mice. Therefore, our hypothesis is that cigarette smoking leads to a decrease in skeletal muscle mass due to the dysregulation of NO-dependent signaling between myofibers and satellite cells that inhibits satellite cells activation and ultimately muscle repair. This will be tested by a series of experiments to determine the role of cigarette smoke exposure on 1) the cross-talk between NO production in myofibers and NO signaling in satellite cells in culture, and 2) the changes in NO signaling that control the ability of muscles to repair after damaging contractions in vivo. Several pharmacological strategies will be tested in vivo to alleviate the NO-dependent dysfunction of muscle repair in consequence of chronic smoking. The outcomes of this project will provide valuable information to develop future strategies to combat the harmful effects of smoking on muscle repair when muscles are subjected to daily activities that lead to muscle injury, and potentially improve quality of life. |
