PT  - JOURNAL ARTICLE
AU  - Luan, Peiling
AU  - D’Amico, Davide
AU  - Andreux, Pénélope A.
AU  - Laurila, Pirkka-Pekka
AU  - Wohlwend, Martin
AU  - Li, Hao
AU  - Imamura de Lima, Tanes
AU  - Place, Nicolas
AU  - Rinsch, Chris
AU  - Zanou, Nadège
AU  - Auwerx, Johan
TI  - Urolithin A improves muscle function by inducing mitophagy in muscular dystrophy
AID  - 10.1126/scitranslmed.abb0319
DP  - 2021 Apr 07
TA  - Science Translational Medicine
PG  - eabb0319
VI  - 13
IP  - 588
4099  - http://stm.sciencemag.org/content/13/588/eabb0319.short
4100  - http://stm.sciencemag.org/content/13/588/eabb0319.full
AB  - Mitochondrial dysfunction has been implicated in Duchenne muscular dystrophy (DMD). Luan and colleagues studied the role of mitophagy (mitochondrial autophagy) in muscle stem cells and DMD. Mitophagy was reduced in muscle biopsies from patients with muscular dystrophies and in mouse and worm models of DMD. Urolithin A, a mitophagy activator, up-regulated mitophagy-related genes and improved mitochondrial respiration, muscle stem cell regeneration and muscle function in models of DMD. This demonstrates how enhancing mitophagy could potentially help treat DMD.Duchenne muscular dystrophy (DMD) is the most common muscular dystrophy, and despite advances in genetic and pharmacological disease-modifying treatments, its management remains a major challenge. Mitochondrial dysfunction contributes to DMD, yet the mechanisms by which this occurs remain elusive. Our data in experimental models and patients with DMD show that reduced expression of genes involved in mitochondrial autophagy, or mitophagy, contributes to mitochondrial dysfunction. Mitophagy markers were reduced in skeletal muscle and in muscle stem cells (MuSCs) of a mouse model of DMD. Administration of the mitophagy activator urolithin A (UA) rescued mitophagy in DMD worms and mice and in primary myoblasts from patients with DMD, increased skeletal muscle respiratory capacity, and improved MuSCs’ regenerative ability, resulting in the recovery of muscle function and increased survival in DMD mouse models. These data indicate that restoration of mitophagy alleviates symptoms of DMD and suggest that UA may have potential therapeutic applications for muscular dystrophies.