title: Targeted inhibition of TGF-β results in an initial improvement but long-term deficit in force production after contraction-induced skeletal muscle injury.
abstract: Transforming growth factor-β (TGF-β) is a proinflammatory cytokine that regulates the response of many tissues following injury. Previous studies in our lab have shown that treating muscles with TGF-β results in a dramatic accumulation of type I collagen, substantial fiber atrophy, and a marked decrease in force production. Because TGF-β promotes atrophy and fibrosis, our objective was to investigate whether the inhibition of TGF-β after injury would enhance the recovery of muscle following injury. We hypothesized that inhibiting TGF-β after contraction-induced injury would improve the functional recovery of muscles by preventing muscle fiber atrophy and weakness, and by limiting the accumulation of fibrotic scar tissue. To test this hypothesis, we induced an injury using a series of in situ lengthening contractions to extensor digitorum longus muscles of mice treated with either a bioneutralizing antibody against TGF-β or a sham antibody. Compared with controls, muscles from mice receiving TGF-β inhibitor showed a greater recovery in force 3 days and 7 days after injury but had a decrease in force compared with controls at the 21-day time point. The early enhancement in force in the TGF-β inhibitor group was associated with an initial improvement in tissue morphology, but, at 21 days, while the control group was fully recovered, the TGF-β inhibitor group displayed an irregular extracellular matrix and an increase in atrogin-1 gene expression. These results indicate that the inhibition of TGF-β promotes the early recovery of muscle function but is detrimental overall to full muscle recovery following moderate to severe muscle injuries.
authors.affiliation: Department of Orthopaedic Surgery, University of Michigan Medical School, Ann Arbor, Michigan 48109-2200, USA.
authors.forename: Jonathan P
authors.initials: JP
authors.lastname: Gumucio
authors.forename: Michael D
authors.initials: MD
authors.lastname: Flood
authors.forename: Anthony C
authors.initials: AC
authors.lastname: Phan
authors.forename: Susan V
authors.initials: SV
authors.lastname: Brooks
authors.forename: Christopher L
authors.initials: CL
authors.lastname: Mendias
mesh_terms: D000818:Animals; D005109:Extracellular Matrix / Q000378:metabolism; D005355:Fibrosis; D051379:Mice; D008810:Mice, Inbred C57BL; D009119:Muscle Contraction / Q000187:drug effects / Q000502:physiology*; D018485:Muscle Fibers, Skeletal / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology / Q000502:physiology; D009124:Muscle Proteins / Q000378:metabolism; D018908:Muscle Weakness / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology*; D009133:Muscular Atrophy / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D020127:Recovery of Function / Q000187:drug effects; D044843:SKP Cullin F-Box Protein Ligases / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D009124:Muscle Proteins; D016212:Transforming Growth Factor beta; C486691:Fbxo32 protein, mouse; D044843:SKP Cullin F-Box Protein Ligases
keywords: atrogin-1; fibroblast specific protein-1; scleraxis; transforming growth factor-β