Glycogen accumulation in smooth muscle of a Pompe disease mouse model

Abstract

Pompe disease is a lysosomal storage disease caused by mutations within the GAA gene, which encodes acid α-glucosidase (GAA)—an enzyme necessary for lysosomal glycogen degradation. A lack of GAA results in an accumulation of glycogen in cardiac and skeletal muscle, as well as in motor neurons. The only FDA approved treatment for Pompe disease—an enzyme replacement therapy (ERT)—increases survival of patients, but has unmasked previously unrecognized clinical manifestations of Pompe disease. These clinical signs and symptoms include tracheo-bronchomalacia, vascular aneurysms, and gastro-intestinal discomfort. Together, these previously unrecognized pathologies indicate that GAA-deficiency impacts smooth muscle in addition to skeletal and cardiac muscle. Thus, we sought to characterize smooth muscle pathology in the airway, vascular, gastrointestinal, and genitourinary in the Gaa −/− mouse model. Increased levels of glycogen were present in smooth muscle cells of the aorta, trachea, esophagus, stomach, and bladder of Gaa −/− mice, compared to wild type mice. In addition, there was an increased abundance of both lysosome membrane protein (LAMP1) and autophagosome membrane protein (LC3) indicating vacuolar accumulation in several tissues. Taken together, we show that GAA deficiency results in subsequent pathology in smooth muscle cells, which may lead to life-threatening complications if not properly treated.

Cross-species evolution of a highly potent AAV variant for therapeutic gene transfer and genome editing

“…GAA enzymatic activity was quantified as previously described 42 , 43 . Briefly, snap-frozen tissues were homogenized using a FastPrep bead system (MP Biomedicals), followed by three cycles of freezing and thawing.…”

From Acid Alpha-Glucosidase Deficiency to Autophagy: Understanding the Bases of POMPE Disease

“…One is the role of lysosomal Besides the abovementioned uncertainties regarding the events linking GAA deficiency and disruption of mTORC1/AMPK function, the available evidence points out that AuP-BU compromises skeletal muscle functionality, but this appears not to be the case for cardiac muscle. Moreover, there is recent evidence of AuP-BU in smooth muscle [21]. Raval et al (2015) mentioned that there is hypertrophy rather than cardiac atrophy during PD.…”

A novel likely pathogenic homozygous RBCK1 variant in dilated cardiomyopathy with muscle weakness

“…This accumulation subsequently leads to neurodegeneration and neurobehavioural disorders 12 . The absence of RBCK1 is associated with glycogen exhibiting longer chains and hyperphosphorylation, comparable with the symptoms seen in Lafora disease (LD) 13 . RBCK1 is part of a system regulating glycogen regulation, including its presence in specific neural regions.…”