title: Use of an antifibrotic agent improves the effect of platelet-rich plasma on muscle healing after injury.
abstract: BACKGROUND
  Muscle contusions are a common type of muscle injury and are frequently encountered in athletes and military personnel. Although these injuries are capable of healing in most instances, incomplete functional recovery often occurs because of the development of fibrosis in the muscle. We hypothesized that a combination of platelet-rich plasma (PRP) injection and oral administration of losartan (an antifibrotic agent) could enhance muscle healing by stimulating muscle regeneration and angiogenesis and by preventing fibrosis in contusion-injured skeletal muscle.
  
  
  METHODS
  Contusion injuries were created in the tibialis anterior muscles of mice. Two treatments were tested, alone and in combination: 20 μL of PRP injected into the contusion site one day after injury, and 10 mg/kg/day of losartan administered beginning three days after injury and continuing until the end point of the experiment. Muscle regeneration and fibrosis development were evaluated by histological analysis, and functional recovery was measured by physiological testing.
  
  
  RESULTS
  Muscle regeneration and muscle function were significantly promoted in the combined PRP + losartan treatment group compared with the other groups. Combined PRP + losartan treatment significantly decreased the expression of phosphorylated Smad2/3 and the development of fibrosis compared with PRP treatment alone, and it increased vascular endothelial growth factor (VEGF) expression and the number of CD31-positive structures compared with losartan treatment alone. Follistatin, a positive regulator of muscle growth, was expressed at a higher level in the PRP + losartan group compared with the other groups.
  
  
  CONCLUSIONS
  PRP + losartan combinatorial therapy improved overall skeletal muscle healing after muscle contusion injury by enhancing angiogenesis and follistatin expression and by reducing the expression of phosphorylated Smad2/3 and the development of fibrosis. These results suggest that blocking the expression of transforming growth factor (TGF)-β1 with losartan improves the effect of PRP therapy on muscle healing after a contusion injury.
  
  
  CONCLUSIONS
  These findings could contribute to the development of biological treatments that aid in the healing of skeletal muscle after injury.
authors.affiliation: Stem Cell Research Center, Department of Orthopaedic Surgery, University of Pittsburgh Medical Center, Bridgeside Point II, Suite 206, 450 Technology Drive, Pittsburgh, PA 15219, USA.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Terada
authors.forename: Shusuke
authors.initials: S
authors.lastname: Ota
authors.forename: Makoto
authors.initials: M
authors.lastname: Kobayashi
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Kobayashi
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Mifune
authors.forename: Koji
authors.initials: K
authors.lastname: Takayama
authors.forename: Michelle
authors.initials: M
authors.lastname: Witt
authors.forename: Gianluca
authors.initials: G
authors.lastname: Vadalà
authors.forename: Nick
authors.initials: N
authors.lastname: Oyster
authors.forename: Takanobu
authors.initials: T
authors.lastname: Otsuka
authors.forename: Freddie H
authors.initials: FH
authors.lastname: Fu
authors.forename: Johnny
authors.initials: J
authors.lastname: Huard
mesh_terms: D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology*; D000818:Animals; D003288:Contusions / Q000188:drug therapy* / Q000473:pathology; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005455:Fluorescent Antibody Technique; D019808:Losartan / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018482:Muscle, Skeletal / Q000293:injuries* / Q000473:pathology; D053657:Platelet-Rich Plasma / Q000187:drug effects*; D012038:Regeneration / Q000187:drug effects*; D053773:Transforming Growth Factor beta1 / Q000378:metabolism*; D014945:Wound Healing / Q000187:drug effects*
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D053773:Transforming Growth Factor beta1; D019808:Losartan