title: Inhibiting TGF-β activity improves respiratory function in mdx mice.
abstract: Respiratory function is the main cause of mortality in patients with Duchenne muscular dystrophy (DMD). Elevated levels of TGF-β play a key role in the pathophysiology of DMD. To determine whether therapeutic attenuation of TGF-β signaling improves respiratory function, mdx mice were treated from 2 weeks of age to 2 months or 9 months of age with either 1D11 (a neutralizing antibody to all three isoforms of TGF-β), losartan (an angiotensin receptor antagonist), or a combination of the two agents. Respiratory function was measured in nonanesthetized mice by plethysmography. The 9-month-old mdx mice had elevated Penh values and decreased breathing frequency, due primarily to decreased inspiratory flow rate. All treatments normalized Penh values and increased peak inspiratory flow, leading to decreased inspiration times and breathing frequency. Additionally, forelimb grip strength was improved after 1D11 treatment at both 2 and 9 months of age, whereas, losartan improved grip strength only at 2 months. Decreased serum creatine kinase levels (significant improvement for all groups), increased diaphragm muscle fiber density, and decreased hydroxyproline levels (significant improvement for 1D11 only) also suggested improved muscle function after treatment. For all endpoints, 1D11 was equivalent or superior to losartan; coadministration of the two agents was not superior to 1D11 alone. In conclusion, TGF-β antagonism may be a useful therapeutic approach for treating DMD patients.
authors.affiliation: Genzyme Corporation, Framingham, Massachusetts, USA. Carol.nelson@genzyme.com
authors.forename: Carol A
authors.initials: CA
authors.lastname: Nelson
authors.forename: R Bridge
authors.initials: RB
authors.lastname: Hunter
authors.forename: Lindsay A
authors.initials: LA
authors.lastname: Quigley
authors.forename: Stefan
authors.initials: S
authors.lastname: Girgenrath
authors.forename: William D
authors.initials: WD
authors.lastname: Weber
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: McCullough
authors.forename: Carol J
authors.initials: CJ
authors.lastname: Dinardo
authors.forename: Kelly A
authors.initials: KA
authors.lastname: Keefe
authors.forename: Lorena
authors.initials: L
authors.lastname: Ceci
authors.forename: Nicholas P
authors.initials: NP
authors.lastname: Clayton
authors.forename: Alison
authors.initials: A
authors.lastname: McVie-Wylie
authors.forename: Seng H
authors.initials: SH
authors.lastname: Cheng
authors.forename: John P
authors.initials: JP
authors.lastname: Leonard
authors.forename: Bruce M
authors.initials: BM
authors.lastname: Wentworth
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D001835:Body Weight / Q000187:drug effects; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism; D003402:Creatine Kinase / Q000097:blood; D003964:Diaphragm / Q000187:drug effects / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D004305:Dose-Response Relationship, Drug; D004656:Enalapril / Q000008:administration & dosage / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D018737:Hand Strength / Q000502:physiology; D006909:Hydroxyproline / Q000378:metabolism; D007249:Inflammation / Q000097:blood / Q000378:metabolism / Q000473:pathology; D019808:Losartan / Q000008:administration & dosage / Q000494:pharmacology; D051379:Mice; D018101:Mice, Inbred mdx; D018485:Muscle Fibers, Skeletal / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D018008:Myogenin / Q000378:metabolism; D009929:Organ Size / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012119:Respiration / Q000187:drug effects; D012129:Respiratory Function Tests; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism
chemical_list: D015415:Biomarkers; D015815:Cell Adhesion Molecules; C503801:Myog protein, mouse; D018008:Myogenin; C082838:Postn protein, mouse; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta; D004656:Enalapril; D003402:Creatine Kinase; D019808:Losartan; D006909:Hydroxyproline