Impaired autophagy correlates with golden retriever muscular dystrophy phenotype

Duchenne muscular dystrophy (DMD) and golden retriever muscular dystrophy (GRMD) are X-linked disorders caused by mutations in the DMD gene. Autophagy was recently identified as a secondary therapeutic target for DMD. We hypothesized that autophagy would be reduced in GRMD.

Autophagic gene and protein expression was assessed in normal and GRMD skeletal muscles and correlated with phenotypic biomarkers.

Muscles were differentially affected. Autophagy gene levels were lower than normal in the GRMD cranial sartorius (CS) but similar in the vastus lateralis (VL). Protein markers of autophagic flux, LC3B-II and p62, were higher in both GRMD muscles, in keeping with impaired autophagy. Protein levels correlated with a more severe phenotype. Autophagic structures were found in necrotic, fast-twitch GRMD myofibers.

Our data suggest that autophagy is impaired in certain GRMD muscles. Differential GRMD CS involvement emphasizes that therapeutic modulation of autophagy could require specific muscle targeting. Muscle Nerve 58: 418-426, 2018.