Inhibition of inflammation with celastrol fails to improve muscle function in dysferlin-deficient A/J mice

JOURNAL OF THE NEUROLOGICAL SCIENCES

卷:356

Article

Dillingham, Blythe C.¹  Klimek, Margaret E. Benny¹  Gernapudi, Ramkishore¹  Rayavarapu, Sree¹  Gallardo, Eduard²  Van der Meulen, Jack H.²  Jordan, Sarah²  Ampong, Beryl²  Gordish-Dressman, Heather²  Spurney, Christopher F.²  Nagaraju, Kanneboyina^1,3 

[1] Childrens Natl Med Ctr, Med Genet Res Ctr, Washington, DC 20010 USA

[2] Hosp Santa Creu & Sant Pau, Inst Recerca, Barcelona 08025, Spain

[3] George Washington Univ, Inst Biomed Sci, Dept Integrat Syst Biol, Washington, DC USA

关键词: Muscular dystrophy;    Skeletal muscle;    Dysferlin;    Celastrol;    NF-kappa B;    Inflammation;   

DOI  :  10.1016/j.jns.2015.06.042

来源: Elsevier

【 摘 要 】

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 ALOlaHsd, 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/JolaHsd 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-alpha when compared to C57BL/6 mice, indicating an activation of NF-kappa B signaling as part of the inflammatory response in dysferlin-deficient muscle. Therefore, we assessed the effect of celastrol (a potent NF-kappa B 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. (C) 2015 Elsevier B.V. All rights reserved.

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