Atg5flox-Derived Autophagy-Deficient Model of Pompe Disease: Does It Tell the Whole Story?

Jeong-A Lim,Hossein Zare,Rosa Puertollano,Nina Raben

doi:10.1016/j.omtm.2017.08.002

Abstract

Defective autophagy is a prominent feature in Pompe disease, an inherited deficiency of acid alpha-glucosidase. An absence of this enzyme leaves cells unable to digest glycogen in the lysosome. The major tissues affected by glycogen accumulation are cardiac and skeletal muscles. The currently available enzyme replacement therapy (ERT) works well in cardiac, but not in skeletal muscle. The disappointing response to therapy is linked to the presence of large areas of autophagic debris in muscle fibers.

Highlights

In the process of studying the pathogenesis of Pompe disease, a severe metabolic myopathy caused by a deficiency of the glycogendegrading lysosomal acid alpha-glucosidase (GAA), we documented the presence of large areas of autophagic debris in the diseased muscle fibers
To dissect the role of autophagic buildup and intralysosomal glycogen accumulation in muscle weakness and wasting in Pompe disease, we generated muscle-specific autophagy-deficient GAA-KO mice. These GAA-KO mice contain a Cre recombinase transgene under the control of the human skeletal actin promoter (HSAcre) and an Atg[5] gene, in which exon 3 is flanked by loxP sites.[4]
Because of the extensive genetic manipulation that was required to create these mice,[3] we made a second line, MLCcre:Atg[7] DKO, as a back-up. Another critical autophagic gene, Atg[7], is excised in muscle by the Cre recombinase driven by the myosin light chain1f (MLC) promoter.[5]

Summary

Introduction

In the process of studying the pathogenesis of Pompe disease, a severe metabolic myopathy caused by a deficiency of the glycogendegrading lysosomal acid alpha-glucosidase (GAA), we documented the presence of large areas of autophagic debris in the diseased muscle fibers. E-mail: puertolr@mail.nih.gov Correspondence: Nina Raben, Laboratory of Muscle Stem Cells and Gene Regulation, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, USA.

Results

Conclusion