title: Investigation of wild-type and mycolactone-negative mutant Mycobacterium ulcerans on skeletal muscle: IGF-1 protects against mycolactone-induced muscle catabolism.
abstract: Buruli ulcer (BU), which is caused by Mycobacterium ulcerans (MU), is an endemic and neglected tropical disease that affects mostly subcutaneous tissues. Skeletal muscle under infected skin is also subject to serious dysfunctions and contractures. The goal of this study was to investigate the effects of an infection with the wild-type M. ulcerans (WT-MU) or the mycolactone-negative Mycobacterium ulcerans (M(neg)-MU) mutant strains on myotubes or fully differentiated skeletal muscles. WT-MU infection decreased by 22% and 29% the maximal muscle force at days 7 and 42 postinfection, respectively, while M(neg)-MU induced no decrease at day 7 postinfection and a small but significant 13% decrease in muscle force at day 42. A 13.2-fold and 4.3-fold increase in neutrophil and macrophage concentrations, respectively, was observed on day 42 following the injection of WT-MU. However, the increases in neutrophil and macrophage concentrations were 2.4-fold and 5.5-fold in M(neg)-MU. Myoblast proliferation decreased by 20%, myotube diameter by 45%, MyHC levels by 32%, while MuRF-1 levels increased by 22.8% when C2C12 cells and WT-MU were cocultured for 48 h at a multiplicity of infection of 5:1. In contrast, M(neg)-MU had no significant effect. Interestingly, the addition of 1,000 ng/ml of IGF-1 to the WT-MU/C2C12 coculture significantly improved all of these biological parameters. The present investigation clearly established that muscle dysfunction and chronic inflammation in the presence of WT-MU are largely caused by the release of mycolactone, and the addition of recombinant IGF-1 was sufficient to alleviate some of the antiproliferative and atrophic effects of mycolactone.
authors.affiliation: Centre de Recherche du Centre Hospitalier Universitaire de Québec-Centre Hospitalier de L'Université Laval, Université Laval, Quebec City, Quebec, Canada.
authors.forename: Sébastien S
authors.initials: SS
authors.lastname: Dufresne
authors.forename: Jérôme
authors.initials: J
authors.lastname: Frenette
mesh_terms: D000818:Animals; D001284:Atrophy; D001427:Bacterial Toxins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival; D015536:Down-Regulation; D005615:Freezing; D015964:Gene Expression Regulation, Bacterial / Q000235:genetics / Q000502:physiology; D007150:Immunohistochemistry; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology*; D007537:Isometric Contraction / Q000187:drug effects; D018942:Macrolides / Q000037:antagonists & inhibitors* / Q000494:pharmacology*; D008297:Male; D008660:Metabolism / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D008870:Microtubules / Q000187:drug effects; D009119:Muscle Contraction / Q000187:drug effects / Q000502:physiology; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000378:metabolism* / Q000648:ultrastructure; D009154:Mutation / Q000502:physiology*; D019911:Mycobacterium ulcerans / Q000235:genetics* / Q000378:metabolism*; D032446:Myoblasts / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D018995:Myosin Heavy Chains / Q000378:metabolism
chemical_list: D001427:Bacterial Toxins; D018942:Macrolides; C117218:mycolactone; D007334:Insulin-Like Growth Factor I; D018995:Myosin Heavy Chains
keywords: Buruli ulcer; Mycobacterium ulcerans; insulin-like growth factor-1; muscle dysfunction; mycolactone