Treatment with a triazole inhibitor of the mitochondrial permeability transition pore fully corrects the pathology of sapje zebrafish lacking dystrophin

Anna Stocco, Natalia Smolina, Patrizia Sabatelli, Justina Šileikytė, Edoardo Artusi, Vincent Mouly, Michael Cohen, Michael Forte, Marco Schiavone, Paolo Bernardi

Research output: Contribution to journalArticlepeer-review

Abstract

High-throughput screening identified isoxazoles as potent but metabolically unstable inhibitors of the mitochondrial permeability transition pore (PTP). Here we have studied the effects of a metabolically stable triazole analog, TR001, which maintains the PTP inhibitory properties with an in vitro potency in the nanomolar range. We show that TR001 leads to recovery of muscle structure and function of sapje zebrafish, a severe model of Duchenne muscular dystrophy (DMD). PTP inhibition fully restores the otherwise defective respiration in vivo, allowing normal development of sapje individuals in spite of lack of dystrophin. About 80 % sapje zebrafish treated with TR001 are alive and normal at 18 days post fertilization (dpf), a point in time when not a single untreated sapje individual survives. Time to 50 % death of treated zebrafish increases from 5 to 28 dpf, a sizeable number of individuals becoming young adults in spite of the persistent lack of dystrophin expression. TR001 improves respiration of myoblasts and myotubes from DMD patients, suggesting that PTP-dependent dysfunction also occurs in the human disease and that mitochondrial therapy of DMD with PTP-inhibiting triazoles is a viable treatment option.

Original languageEnglish (US)
Article number105421
JournalPharmacological Research
Volume165
DOIs
StatePublished - Mar 2021

Keywords

  • Duchenne muscular dystrophy
  • Mitochondria
  • Permeability transition
  • Respiration
  • Triazole

ASJC Scopus subject areas

  • Pharmacology

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