Limited repair and structural damages displayed by skeletal muscles loaded with mycolactone.
Mycolactone produced by Mycobacterium ulcerans is the toxin responsible for most of the pathology in Buruli ulcer, the cutaneous signature of a complex disease. Although mycolactone cytopathicity is well described in various in vitro and in vivo models, the effect of this molecule on mammalian skeletal muscles has not been addressed. This is particularly surprising since muscle damage is characteristic of severe Buruli ulcer. We have thus investigated the impact of mycolactone on the mouse soleus muscle during degenerative and regenerative phases. Mice were intramuscularly injected with 300 microg of mycolactone and soleus muscles assessed histologically, biochemically and functionally at 7 and 42 days post-injection. Our results show that mycolactone induces local acute and chronic inflammatory responses which are respectively associated with a 65% and 68% decrease in maximal isometric force production (P(0)) relative to sham injections. In addition, muscle stiffness and total hydroxyproline content rose by 46% and 134% at day 42 relative to sham injections indicating an extensive fibrotic process in injured soleus muscles. Histological observations demonstrate significant muscle necrosis and atrophy with limited signs of regeneration. Together, our data indicate that mycolactone not only induces muscle damage but also prevents muscle regeneration to occur. These results may help to explain why patients with Buruli ulcer, experience muscle weakness and contracture.
Houngbédji
Germain Mabèrou
GM
Centre de Recherche du Centre Hospitalier de l'Université Laval, 2705 boulevard Laurier, bureau RC-9500, Québec (Qc) G1V 4G2, Canada.
Côté
Claude H
CH
Small
Pamela L C
PL
Frenette
Jérôme
J
D000818:Animals; D001427:Bacterial Toxins / Q000008:administration & dosage / Q000302:isolation & purification / Q000633:toxicity*; D054312:Buruli Ulcer / Q000473:pathology / Q000503:physiopathology; D005355:Fibrosis / Q000473:pathology; D006801:Humans; D007249:Inflammation / Q000473:pathology; D018942:Macrolides; D008297:Male; D051379:Mice; D018908:Muscle Weakness; D018482:Muscle, Skeletal / Q000187:drug effects / Q000473:pathology* / Q000503:physiopathology*; D009133:Muscular Atrophy; D019911:Mycobacterium ulcerans / Q000737:chemistry*; D009336:Necrosis / Q000473:pathology
D001427:Bacterial Toxins; D018942:Macrolides; C117218:mycolactone