title: Inhibition of inflammation with celastrol fails to improve muscle function in dysferlin-deficient A/J mice.
abstract: The dysferlin-deficient A/J mouse strain represents a homologous model for limb-girdle muscular dystrophy 2B. We evaluated the disease phenotype in 10 month old A/J mice compared to two dysferlin-sufficient, C57BL/6 and A/JOlaHsd, mouse lines to determine which functional end-points are sufficiently sensitive to define the disease phenotype for use in preclinical studies in the A/J strain. A/J mice had significantly lower open field behavioral activity (horizontal activity, total distance, movement time and vertical activity) when compared to C57BL/6 and A/JoIaHsd mice. Both A/J and A/JOIaHsd mice showed decreases in latency to fall with rotarod compared to C57BL/6. No changes were detected in grip strength, force measurements or motor coordination between these three groups. Furthermore, we have found that A/J muscle shows significantly increased levels of the pro-inflammatory cytokine TNF-α when compared to C57BL/6 mice, indicating an activation of NF-κB signaling as part of the inflammatory response in dysferlin-deficient muscle. Therefore, we assessed the effect of celastrol (a potent NF-κB inhibitor) on the disease phenotype in female A/J mice. Celastrol treatment for four months significantly reduced the inflammation in A/J muscle; however, it had no beneficial effect in improving muscle function, as assessed by grip strength, open field activity, and in vitro force contraction. In fact, celastrol treated mice showed a decrease in body mass, hindlimb grip strength and maximal EDL force. These findings suggest that inhibition of inflammation alone may not be sufficient to improve the muscle disease phenotype in dysferlin-deficient mice and may require combination therapies that target membrane stability to achieve a functional improvement in skeletal muscle.
authors.affiliation: Research Center for Genetic Medicine, Children's National Medical Center, 111 Michigan Ave NW, Washington, D.C., USA.
authors.forename: Blythe C
authors.initials: BC
authors.lastname: Dillingham
authors.affiliation: Research Center for Genetic Medicine, Children's National Medical Center, 111 Michigan Ave NW, Washington, D.C., USA.
authors.forename: Margaret E
authors.initials: ME
authors.lastname: Benny Klimek
authors.affiliation: Research Center for Genetic Medicine, Children's National Medical Center, 111 Michigan Ave NW, Washington, D.C., USA.
authors.forename: Ramkishore
authors.initials: R
authors.lastname: Gernapudi
authors.affiliation: Research Center for Genetic Medicine, Children's National Medical Center, 111 Michigan Ave NW, Washington, D.C., USA.
authors.forename: Sree
authors.initials: S
authors.lastname: Rayavarapu
authors.affiliation: Institut de Recerca Hospital de la Santa Creu i Sant Pau. U.A.B.C./Pare Claret, 167 08025 Barcelona, Spain.
authors.forename: Eduard
authors.initials: E
authors.lastname: Gallardo
authors.affiliation: Institut de Recerca Hospital de la Santa Creu i Sant Pau. U.A.B.C./Pare Claret, 167 08025 Barcelona, Spain.
authors.forename: Jack H
authors.initials: JH
authors.lastname: Van der Meulen
authors.affiliation: Institut de Recerca Hospital de la Santa Creu i Sant Pau. U.A.B.C./Pare Claret, 167 08025 Barcelona, Spain.
authors.forename: Sarah
authors.initials: S
authors.lastname: Jordan
authors.affiliation: Institut de Recerca Hospital de la Santa Creu i Sant Pau. U.A.B.C./Pare Claret, 167 08025 Barcelona, Spain.
authors.forename: Beryl
authors.initials: B
authors.lastname: Ampong
authors.affiliation: Institut de Recerca Hospital de la Santa Creu i Sant Pau. U.A.B.C./Pare Claret, 167 08025 Barcelona, Spain.
authors.forename: Heather
authors.initials: H
authors.lastname: Gordish-Dressman
authors.affiliation: Institut de Recerca Hospital de la Santa Creu i Sant Pau. U.A.B.C./Pare Claret, 167 08025 Barcelona, Spain.
authors.forename: Christopher F
authors.initials: CF
authors.lastname: Spurney
authors.affiliation: Research Center for Genetic Medicine, Children's National Medical Center, 111 Michigan Ave NW, Washington, D.C., USA; Department of Integrative Systems Biology, Institute for Biomedical Sciences, The George Washington University, 2300 Eye Street, N.W., Ross 605, Washington, D.C., USA. Electronic address: knagaraju@childrensnational.org.
authors.forename: Kanneboyina
authors.initials: K
authors.lastname: Nagaraju
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D000073939:Dysferlin; D004452:Echocardiography; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D066298:In Vitro Techniques; D007249:Inflammation / Q000188:drug therapy* / Q000209:etiology; D008297:Male; D008565:Membrane Proteins / Q000172:deficiency*; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D053580:Muscle Strength / Q000187:drug effects; D018482:Muscle, Skeletal / Q000187:drug effects / Q000473:pathology; D049288:Muscular Dystrophies, Limb-Girdle / Q000150:complications / Q000188:drug therapy*; D053978:Pentacyclic Triterpenes; D014315:Triterpenes / Q000633:toxicity*
chemical_list: D016207:Cytokines; C497505:Dysf protein, mouse; D000073939:Dysferlin; D008565:Membrane Proteins; D053978:Pentacyclic Triterpenes; D014315:Triterpenes; C050414:celastrol
keywords: Celastrol; Dysferlin; Inflammation; Muscular dystrophy; NF-κB; Skeletal muscle