title: Effects of N-acetylcysteine on skeletal muscle structure and function in a mouse model of peripheral arterial insufficiency.
abstract: OBJECTIVE
  Abnormalities in skeletal muscle structure and function are important contributors to exercise intolerance and functional decline in peripheral arterial disease. In this study, we tested the hypothesis that administration of N-acetylcysteine (NAC) would improve fatigue resistance and ameliorate the histopathological changes in skeletal muscle in a mouse model of peripheral arterial disease. We also anticipated that NAC treatment would lower the levels of biomarkers of oxidative damage in the ischemic muscle.
  
  
  METHODS
  Male Balb/c mice were subjected to bilateral ligation of the femoral artery and, after 2 weeks of recovery, received daily intraperitoneal injections of either NAC (150 mg/kg) or saline for 15 days. At the end of the treatment, the extensor digitorium longus (EDL) and soleus muscles were excised for assessment of contractile function in vitro and histological analysis. Free malondialdehyde and protein carbonyl levels were measured in the gastrocnemius muscle.
  
  
  RESULTS
  In the soleus muscle, force after 10 minutes of submaximal tetanic stimulation (60 Hz, 300 ms trains, 0.3 trains/s) was higher (P < .05) in NAC-treated animals (45% ± 3% of the initial value; n = 7) when compared with controls (30.3% ± 3%; n = 8). No differences were found in fatigue development between groups in the EDL muscle (ligated NAC, 35.7% ± 1.9%; ligated saline, 37.5% ± 1.1%). In addition, there was a tendency for lower levels of connective tissue deposition in the soleus of animals treated with NAC (n = 6) when compared with those that received only saline (n = 9) (ligated NAC, 16% ± 2% vs ligated saline, 24% ± 2%; P = .057). No differences were found in lipid peroxidation or protein carbonyl levels between ligated saline and ligated NAC groups.
  
  
  CONCLUSIONS
  Taken together, these results indicate that treatment with NAC improves fatigue resistance in the soleus but not the EDL muscle in a model of peripheral arterial insufficiency.
  
  
  CONCLUSIONS
  Despite the increasing burden of peripheral arterial disease (PAD) and its detrimental consequences on the quality of life of the patients, few pharmacological therapies have shown to evoke meaningful effects on functional performance in these individuals. N-acetylcysteine is approved for clinical use, has minimal side effects and most important, has shown to consistently improve exercise performance in animals and humans. In this study, we showed, for the first time, that treatment with this drug at a dose amenable for clinical application evoked marked effects on fatigue resistance in the soleus muscle in a mouse model of PAD. These encouraging findings set the stage for translational studies to determine the acute and long-term impact of this drug on walking capacity in patients with PAD.
authors.affiliation: Department of Biophysics, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, Brazil.
authors.forename: Bruno T
authors.initials: BT
authors.lastname: Roseguini
authors.affiliation: Department of Biophysics, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, Brazil.
authors.forename: Leonardo M
authors.initials: LM
authors.lastname: Silva
authors.affiliation: Institute of Physical Activity and Sports Sciences (ICAFE), Universidade Cruzeiro do Sul, São Paulo, Brazil.
authors.forename: Tatiana G
authors.initials: TG
authors.lastname: Polotow
authors.affiliation: Institute of Physical Activity and Sports Sciences (ICAFE), Universidade Cruzeiro do Sul, São Paulo, Brazil.
authors.forename: Marcelo P
authors.initials: MP
authors.lastname: Barros
authors.affiliation: Department of Pharmacology, Section of Natural Products, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, Brazil.
authors.forename: Caden
authors.initials: C
authors.lastname: Souccar
authors.affiliation: Department of Biophysics, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, Brazil. Electronic address: sang.han@unifesp.br.
authors.forename: Sang W
authors.initials: SW
authors.lastname: Han
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology*; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D015415:Biomarkers / Q000378:metabolism; D003094:Collagen / Q000378:metabolism; D017079:Exercise Tolerance / Q000187:drug effects; D005263:Femoral Artery / Q000601:surgery; D008026:Ligation; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D008807:Mice, Inbred BALB C; D009119:Muscle Contraction / Q000187:drug effects; D018763:Muscle Fatigue / Q000187:drug effects*; D018482:Muscle, Skeletal / Q000098:blood supply* / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D018384:Oxidative Stress / Q000187:drug effects; D058729:Peripheral Arterial Disease / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D050050:Protein Carbonylation / Q000187:drug effects; D020127:Recovery of Function; D013997:Time Factors
chemical_list: D000975:Antioxidants; D015415:Biomarkers; D003094:Collagen; D000111:Acetylcysteine