Low-Intensity Training and the C5a Complement Antagonist NOX-D21 Rescue the mdx Phenotype through Modulation of Inflammation.
Inflammatory events occurring in dystrophic muscles contribute to the progression of Duchenne muscular dystrophy (DMD). Low-intensity training (LIT) attenuates the phenotype of mdx mice, an animal model for DMD. Therefore, we postulated that LIT could have anti-inflammatory properties. We assessed levels of inflammatory cytokines and infiltrated immune cells in gastrocnemius muscle of mdx mice after LIT. We detected high levels of complement component C5a, chemokine ligand (CCL) 2, CD68+monocytes/macrophages, and proinflammatory M1 macrophages in muscles of mdx mice. LIT decreased CCL2 levels, increased CD68+cell numbers, and shifted the macrophage population to the regenerative M2 type. We investigated whether inhibition of C5a or CCL2 with L-aptamers could mimic the effects of LIT. Although no effect of CCL2 inhibition was detected, treatment with the C5a inhibitor, NOX-D21, rescued the phenotype of nonexercised mdx mice, but not of exercised ones. In both cases, the level of CD68+cells increased and macrophage populations leaned toward the inflammatory M1 type. In muscles of nonexercised treated mice, the level of IL-1 receptor antagonist increased, damage decreased, and fibers were switched toward the glycolytic fast type; in muscles of exercised mice, fibers were switched to the oxidative slow type. These results reveal the effects of LIT on the inflammatory status of mdx mice and suggest that NOX-D21 could be an anti-inflammatory drug for DMD.
Department of Molecular Therapy, National Institute of Neuroscience, National Centre of Neurology and Psychiatry, Tokyo, Japan.
Janek
J
Hyzewicz
Department of Molecular Therapy, National Institute of Neuroscience, National Centre of Neurology and Psychiatry, Tokyo, Japan.
Jun
J
Tanihata
Department of Molecular Therapy, National Institute of Neuroscience, National Centre of Neurology and Psychiatry, Tokyo, Japan.
Mutsuki
M
Kuraoka
Department of Molecular Therapy, National Institute of Neuroscience, National Centre of Neurology and Psychiatry, Tokyo, Japan.
Yuko
Y
Nitahara-Kasahara
Department of Molecular Therapy, National Institute of Neuroscience, National Centre of Neurology and Psychiatry, Tokyo, Japan.
Teiva
T
Beylier
Laboratory of Pharmacology, University of Geneva, Geneva, Switzerland.
Urs T
UT
Ruegg
Drug Discovery and Preclinical Development, NOXXON Pharma, Berlin, Germany.
Axel
A
Vater
Department of Molecular Therapy, National Institute of Neuroscience, National Centre of Neurology and Psychiatry, Tokyo, Japan. Electronic address: takeda@ncnp.go.jp.
Shin'ichi
S
Takeda
D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D015214:Antigens, Differentiation, Myelomonocytic / Q000378:metabolism; D052157:Aptamers, Nucleotide / Q000494:pharmacology; D018932:Chemokine CCL2 / Q000037:antagonists & inhibitors; D015936:Complement C5a / Q000037:antagonists & inhibitors*; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D004734:Energy Metabolism / Q000502:physiology; D005552:Forelimb; D008264:Macrophages / Q000502:physiology; D008297:Male; D018101:Mice, Inbred mdx; D053580:Muscle Strength / Q000502:physiology; D018482:Muscle, Skeletal / Q000502:physiology; D009137:Muscular Dystrophy, Animal / Q000378:metabolism* / Q000503:physiopathology; D009220:Myositis / Q000503:physiopathology / Q000517:prevention & control; D010641:Phenotype; D010805:Physical Conditioning, Animal / Q000502:physiology*; D013550:Swimming / Q000502:physiology; D000097382:CD68 Molecule
D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D052157:Aptamers, Nucleotide; D018932:Chemokine CCL2; D015936:Complement C5a; D016207:Cytokines; C067980:CD68 antigen, human; D000097382:CD68 Molecule; C491768:Ccl2 protein, mouse; C000621182:NOX-D21; C528578:NOX-E36-3'PEG, mouse