Long-term administration of the TNF blocking drug Remicade (cV1q) to mdx mice reduces skeletal and cardiac muscle fibrosis, but negatively impacts cardiac function.
Duchenne muscular dystrophy (DMD) is a degenerative skeletal muscle disease caused by mutations in the gene encoding dystrophin (DYS). Tumor necrosis factor (TNF) has been implicated in the pathogenesis since short-term treatment of mdx mice with TNF blocking drugs proved beneficial; however, it is not clear whether long-term treatment will also improve long-term outcomes of fibrosis and cardiac health. In this investigation, short and long-term dosing studies were carried out using the TNF blocking drug Remicade and a variety of outcome measures were assessed. Here we show no demonstrable benefit to muscle strength or morphology with 10mg/kg or 20mg/kg Remicade; however, 3mg/kg produced positive strength benefits. Remicade treatment correlated with reductions in myostatin mRNA in the heart, and concomitant reductions in cardiac and skeletal fibrosis. Surprisingly, although Remicade treated mdx hearts were less fibrotic, reductions in LV mass and ejection fraction were also observed, and these changes coincided with reductions in AKT phosphorylation on threonine 308. Thus, TNF blockade benefits mdx skeletal muscle strength and fibrosis, but negatively impacts AKT activation, leading to deleterious changes to dystrophic heart function. These studies uncover a previously unknown relationship between TNF blockade and alteration of muscle growth signaling pathways.
Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA; Center for Duchenne Muscular Dystrophy at UCLA, Los Angeles, CA 90095, USA.
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NV
Ermolova
Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA; Center for Duchenne Muscular Dystrophy at UCLA, Los Angeles, CA 90095, USA.
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L
Martinez
Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA; Center for Duchenne Muscular Dystrophy at UCLA, Los Angeles, CA 90095, USA.
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SA
Vetrone
Department of Physiology, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA.
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MC
Jordan
Department of Physiology, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA.
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KP
Roos
Department of Physiology, University of Pennsylvania, Philadelphia, PA 19104, USA; Paul Wellstone Muscular Dystrophy Center, Philadelphia, PA 19104, USA.
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HL
Sweeney
Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA; Center for Duchenne Muscular Dystrophy at UCLA, Los Angeles, CA 90095, USA; Paul Wellstone Muscular Dystrophy Center, Philadelphia, PA 19104, USA. Electronic address: mspencer@mednet.ucla.edu.
M J
MJ
Spencer
D000367:Age Factors; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D003964:Diaphragm / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D004305:Dose-Response Relationship, Drug; D005355:Fibrosis / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology; D006321:Heart / Q000187:drug effects* / Q000503:physiopathology; D000069285:Infliximab; D018101:Mice, Inbred mdx; D053580:Muscle Strength / Q000187:drug effects / Q000502:physiology; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000473:pathology / Q000503:physiopathology; D009137:Muscular Dystrophy, Animal / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D009206:Myocardium / Q000473:pathology; D055435:Myostatin / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000378:metabolism
D000894:Anti-Inflammatory Agents, Non-Steroidal; D000911:Antibodies, Monoclonal; C525912:Mstn protein, mouse; D055435:Myostatin; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D000069285:Infliximab; D051057:Proto-Oncogene Proteins c-akt
AKT; Inflammation; Muscular dystrophy; Myostatin; Signaling; Treatment; mdx mouse