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Molecular Mechanisms Underlying the Muscle Response to Exercise-Induced Muscle Damage in Chronic Cigarette Smokers

Smoking increases risk for musculoskeletal injury and protracts healing. The underlying mechanisms have not been explored, yet dysregulated inflammatory responses may contribute. To investigate these risks, Study 1 of this dissertation monitored typical responses to muscle damaging eccentric contractions (ECC) in smokers and nonsmokers. Smokers experienced greater muscle fatigue both during and immediately after ECC and greater delayed hyperalgesia, a phenomenon known as delayed onset muscle soreness (DOMS), than did non-smokers. DOMS (driven by inflammation) peaks 48h after ECC, when there is a shift from pro- to anti-inflammatory signaling; thus I chose to investigate this time further in smokers. The “late inflammation” time point is relatively unstudied mechanistically. Therefore, in Study 2 I further characterized the post-ECC muscle response in non-smokers and focused on hyperalgesic pathways. Transcriptome analyses revealed greater proliferation and pro-inflammatory signaling at 3h, which returned to baseline by 48h. Activity of key regulatory pathways canonical (p65) nuclear factor kappa-beta (NFκB) and extracellular regulated kinase (ERK)1/2 mimicked the pro- (activated) to anti- viii inflammatory (de-activated) shift. In addition, nerve growth factor (NGF), a hyperalgesic-modifier, was also induced. Further testing revealed suppressed 48h p65 activity. In Study 3 I tested these pathways, and non-canonical NFκB (REL-B) signaling (specifies oxidative muscle fibers), in skeletal muscle from smokers and non-smokers 48h post-ECC. Smokers had fewer oxidative (Type I) muscle fibers. Further, REL-B, enhanced in non-smokers at 48h, was suppressed in smokers. These findings may explain the greater fatigue in smokers, which can increase risk for injury. p65 activity, suppressed at 48h in non-smokers, was unchanged in smokers, suggesting delayed pro-inflammatory resolution. Active and total ERK levels were suppressed, overall, in smokers. While there were no differences in NGF levels or colocalization with the TrkA receptor between smokers and non-smokers, smokers did express higher p75NTR receptor levels, which may activate NFκB and promote hyperalgesia. NGF/p75NTR co-localization at 48h post-ECC decreased in nonsmokers but increased in smokers. Higher DOMS, NGF, and NFκB signaling may indicate prolonged pro-inflammatory signaling, delayed resolution, and protracted healing in smokers. This dissertation provides insights into mechanisms that appear to place smokers at greater risk for musculoskeletal injury and impaired healing.