|Ph.D Student||Rom Oren|
|Subject||The Effects of Cigarette Smoke on Catabolism of|
Skeletal Muscle - Implications to Sarcopenia
|Department||Department of Medicine||Supervisors||Professor Abraham Reznick|
|Professor Dror Aizenbud|
|Full Thesis text|
Cigarette smoking has been identified as a risk factor for sarcopenia, the age-related loss of skeletal muscle mass and strength. This study aimed to investigate the mechanisms by which cigarette smoke (CS) induces muscle catabolism and to identify components of CS that may be responsible. Also, this study aimed to investigate the effects of smoking versus smoking cessation on muscle mass, strength and body composition (BC).
Skeletal myotubes differentiated from the C2 myoblast cell-line were exposed to CS and CS components that have been suggested to damage skeletal muscle - the aldehydes acetaldehyde and acrolein and the reactive nitrogen species peroxynitrite. Their effects on oxidative stress, p38 MAPK and NF-kB pathways, the ubiquitin-proteasome system and breakdown of muscle proteins were studied using microscopy, Western blotting and qPCR.
A clinical study of 81 adult smokers recruited from the smoking cessation program of
Clalit Health Services was conducted. Measurements were held at the beginning of the program and after 12 months. BC was assessed by dual-energy X-ray absorptiometry and bioelectrical-impedance analysis. Muscle strength was measured by handgrip dynamometry and one-repetition maximum tests. Dietary intake and physical activity were estimated by questionnaires and smoking status was determined by urine cotinine levels. Linear regression models were used to assess the effect of smoking versus smoking cessation.
Exposure of myotubes to CS caused increased oxidative stress and activation of the p38 MAPK and NF-kB pathways which led to the up-regulation of MAFbx/atrogin-1 and MuRF1. CS caused a time- and dose-dependent degradation of myosin heavy chain and reduction of myotube diameter. Pretreatment with N-acetylcysteine, essential amino acid leucine and inhibitors of p38 MAPK, NF-kB and the proteasome abolished the effects of CS. Exposure of myotubes to acrolein and peroxynitrite but not to acetaldehyde activated a similar catabolic pathway as CS exposure.
41 participants completed all measurements (76% smokers; 24% quitters). Adjusting for dietary intake and physical activity changes, significant increases in body weight, muscle mass, fat mass, bone mineral density and muscle strength were found in quitters compared with smokers.
The in vitro study provided a cellular mechanism for the deleterious effects of CS on skeletal muscle and suggested that acrolein and peroxynitrite but not acetaldehyde may be responsible for CS-induced muscle catabolism. The clinical study demonstrated that smoking cessation is associated with increased muscle mass, strength and bone density compared with smoking continuation. Therefore, smoking cessation may be a possible strategy to delay or prevent sarcopenia.