title: Nicotine in combination with a high-fat diet causes intramyocellular mitochondrial abnormalities in male mice.
abstract: Smoking is a major risk factor for diabetes, cardiovascular disease, and nonalcoholic fatty liver disease. The health risk associated with smoking can be exaggerated by obesity. We hypothesize that nicotine when combined with a high-fat diet (HFD) can also cause ectopic lipid accumulation in skeletal muscle, similar to recently observed hepatic steatosis. Adult C57BL6 male mice were fed a normal chow diet or HFD and received twice-daily ip injections of nicotine (0.75 mg/kg body weight) or saline for 10 weeks. Transmission electron microscopy of the gastrocnemius muscle revealed substantial intramyocellular lipid accumulation in close association with intramyofibrillar mitochondria along with intramyofibrillar mitochondrial swelling and vacuolization in nicotine-treated mice on an HFD compared with mice on an HFD treated with saline. These abnormalities were reversed by acipimox, an inhibitor of lipolysis. Mechanistically, the detrimental effect of nicotine plus HFD on skeletal muscle was associated with significantly increased oxidative stress, plasma free fatty acid, and muscle triglyceride levels coupled with inactivation of AMP-activated protein kinase and activation of its downstream target, acetyl-coenzyme A-carboxylase. We conclude that 1) greater oxidative stress together with inactivation of AMP-activated protein kinase mediates the effect of nicotine on skeletal muscle abnormalities in diet-induced obesity and 2) adipose tissue lipolysis is an important contributor of muscle steatosis and mitochondrial abnormalities.
authors.affiliation: Division of Endocrinology, Metabolism, and Molecular Medicine, Department of Internal Medicine (I.S.-H., T.C.F., C.-S.S., D.L., R.I., A.P.S.-H.), Charles R. Drew University of Medicine and Science, Los Angeles, California 90059; and David Geffen School of Medicine at University of California (I.S.-H., T.C.F.), Los Angeles, Los Angeles, California 90095.
authors.forename: Indrani
authors.initials: I
authors.lastname: Sinha-Hikim
authors.forename: Theodore C
authors.initials: TC
authors.lastname: Friedman
authors.forename: Chang-Sung
authors.initials: CS
authors.lastname: Shin
authors.forename: Desean
authors.initials: D
authors.lastname: Lee
authors.forename: Rasheed
authors.initials: R
authors.lastname: Ivey
authors.forename: Amiya P
authors.initials: AP
authors.lastname: Sinha-Hikim
mesh_terms: D000103:Acetyl-CoA Carboxylase / Q000378:metabolism; D000273:Adipose Tissue / Q000378:metabolism; D000818:Animals; D001835:Body Weight; D059305:Diet, High-Fat; D005230:Fatty Acids, Nonesterified / Q000378:metabolism; D008066:Lipolysis; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D046529:Microscopy, Electron, Transmission; D008928:Mitochondria / Q000187:drug effects* / Q000473:pathology*; D018485:Muscle Fibers, Skeletal / Q000473:pathology / Q000648:ultrastructure*; D018482:Muscle, Skeletal / Q000166:cytology / Q000378:metabolism; D009538:Nicotine / Q000008:administration & dosage*; D009765:Obesity; D018384:Oxidative Stress; D011719:Pyrazines / Q000737:chemistry; D012307:Risk Factors; D012907:Smoking; D014280:Triglycerides / Q000378:metabolism
chemical_list: D005230:Fatty Acids, Nonesterified; D011719:Pyrazines; D014280:Triglycerides; D009538:Nicotine; D000103:Acetyl-CoA Carboxylase; C027696:acipimox