title: Electrical Stimulation Based on Chronaxie Increases Fibrosis and Modulates TWEAK/Fn14, TGF-β/Myostatin, and MMP Pathways in Denervated Muscles.
abstract: OBJECTIVE
  The aim of this work was to investigate the effects of electrical stimulation (ES) of denervated muscles of rat in neuromuscular performance, muscle atrophy, and fibrosis formation.
  
  
  METHODS
  Wistar rats were divided into normal (N), 7- or 15-day denervation (D7d and D15d), D7d or D15d plus ES (DES7d and DES15d, respectively). Sciatic nerves were crushed causing muscle denervation. Two hundred muscle contractions were electrically induced daily by surface electrodes, considering muscle chronaxie. Sciatic functional index was used to determine neuromuscular performance during walking. The muscle fiber cross-sectional area and percentage of connective tissue were assessed by light microscopy. Molecular markers of extracellular matrix production and remodeling were evaluated. Metalloproteinase (MMP) activity was assessed by zymography, and TWEAK, Fn14, myostatin, and transforming growth factor (TGF)-β gene expressions were determined by real-time PCR.
  
  
  RESULTS
  Electrical stimulation impaired natural recovery of walking at 15 days. In addition, ES induced fibrosis and accentuated muscle atrophy in denervated muscles. Although ES reduced the accumulation of TWEAK and myostatin expressions, it up-regulated Fn14 and TGF-β in a time-dependent manner. Electrical stimulation also increased the activity of MMP-2 compared to the other groups (P < 0.05).
  
  
  CONCLUSIONS
  Electrical stimulation applied to denervated muscles induced muscle fibrosis and atrophy, as well as loss of performance. The TWEAK/Fn14 system, TGF-beta/myostatin pathway, and MMP activity seem to be involved in these deleterious changes.
authors: From the Laboratory of Neurological Physiotherapy Research (LaFiN), Department of Physiotherapy (DFisio), Federal University of São Carlos (UFSCar), São Carlos, São Paulo, Brazil.
authors: Clara Maria
authors: CM
authors: Pinheiro-Dardis
authors: Thiago Luiz
authors: TL
authors: Russo
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D002907:Chronaxy; D000074049:Cytokine TWEAK; D015536:Down-Regulation; D004558:Electric Stimulation; D005355:Fibrosis / Q000209:etiology; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D023421:Models, Animal; D009121:Muscle Denervation; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology; D009133:Muscular Atrophy / Q000209:etiology; D055435:Myostatin / Q000378:metabolism; D017208:Rats, Wistar; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism; D000074050:TWEAK Receptor; D016212:Transforming Growth Factor beta / Q000378:metabolism; D048069:Tumor Necrosis Factors / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D051017:Apoptosis Regulatory Proteins; D000074049:Cytokine TWEAK; D008565:Membrane Proteins; C525913:Mstn protein, rat; D055435:Myostatin; D018124:Receptors, Tumor Necrosis Factor; D000074050:TWEAK Receptor; C000613300:Tnfrsf12a protein, rat; C497771:Tnfsf12 protein, rat; D016212:Transforming Growth Factor beta; D048069:Tumor Necrosis Factors; D020778:Matrix Metalloproteinase 2