title: Losartan administration reduces fibrosis but hinders functional recovery after volumetric muscle loss injury.
abstract: Losartan is a Food and Drug Administration approved antihypertensive medication that is recently emerging as an antifibrotic therapy. Previously, losartan has been successfully used to reduce fibrosis and improve both muscle regeneration and function in several models of recoverable skeletal muscle injuries, such as contusion and laceration. In this study, the efficacy of losartan treatment in reducing fibrosis and improving regeneration was determined in a Lewis rat model of volumetric muscle loss (VML) injury. VML has been defined as the traumatic or surgical loss of skeletal muscle with resultant functional impairment. It is among the top 10 causes for wounded service members to be medically retired from the military. This study shows that, after several weeks of recovery, VML injury results in little to no muscle regeneration, but is marked by persistent inflammation, chronic upregulation of profibrotic markers and extracellular matrix (i.e., collagen type I), and fat deposition at the defect site, which manifest irrecoverable deficits in force production. Losartan administration at 10 mg·kg(-1)·day(-1) was able to modulate the gene expression of fibrotic markers and was also effective at reducing fibrosis (i.e., the deposition of collagen type I) in the injured muscle. However, there were no improvements in muscle regeneration, and deleterious effects on muscle function were observed instead. We propose that, in the absence of regeneration, reduction in fibrosis worsens the ability of the VML injured muscle to transmit forces, which ultimately results in decreased muscle function.
authors.affiliation: US Army Institute of Surgical Research, Extremity Trauma and Regenerative Medicine, Fort Sam Houston, Texas.
authors.forename: Koyal
authors.initials: K
authors.lastname: Garg
authors.affiliation: US Army Institute of Surgical Research, Extremity Trauma and Regenerative Medicine, Fort Sam Houston, Texas.
authors.forename: Benjamin T
authors.initials: BT
authors.lastname: Corona
authors.affiliation: US Army Institute of Surgical Research, Extremity Trauma and Regenerative Medicine, Fort Sam Houston, Texas thomas.j.walters22.civ@mail.mil.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Walters
mesh_terms: D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology*; D000818:Animals; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005355:Fibrosis; D005786:Gene Expression Regulation; D018836:Inflammation Mediators / Q000378:metabolism; D019808:Losartan / Q000494:pharmacology*; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism; D053580:Muscle Strength / Q000187:drug effects; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D009135:Muscular Diseases / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D009929:Organ Size; D011917:Rats, Inbred Lew; D020127:Recovery of Function; D012038:Regeneration / Q000187:drug effects*; D013997:Time Factors
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D018836:Inflammation Mediators; D009124:Muscle Proteins; D019808:Losartan
keywords: fibrosis; losartan; regeneration; volumetric muscle loss