Acid alpha-glucosidase (GAA) deficiency (Pompe's disease) is an autosomal recessive inherited disease that results from mutations in the GAA gene preventing or reducing the normal breakdown of glycogen in lysosomes. The primary defect occurs in cardiac and skeletal muscle and depending upon the degree of residual GAA enzymatic activity results in a spectrum of phenotypes that include a rapid fatal infantile disorder, juvenile and a late-onset adult myopathy. The infantile form presents as hypotonia with accumulation of glycogen in skeletal and heart muscle, and death due to cardiorespiratory failure. In addition, the classical infantile-onset form results in hepatomegaly due to increased glycogen deposition within the liver. Adult individuals with the slowly progressive form develop severe skeletal muscle weakness and eventually respiratory failure. Glycolytic type II muscle fibers (white) are primarily affected in Pompe's disease whereas oxidative type I muscle fibers (red) are relatively spared. Recent studies have observed that Pompe mice display defective skeletal muscle macroautophagy. Macroautophagy is a complex process by which organelles (ie: mitochondria), macromolecules (ie: glycogen) and cytoplasmic components are entrapped into autophagosomes that fuse with the lysosome for breakdown and release of individual molecular components. Glycolytic type II muscle fibers (white muscle) are primarily affected in Pompe's disease and accumulate autophagic vacuoles whereas oxidative type I muscle fibers (red) are much less unaffected. The observation that GGA deficiency results in the accumulation of autophgic vacuoles suggests macroautophagy initiation occurs normally but with a defect in late macrophage events, ie: lysosomal fusion. This raises several novel hypotheses for the mechanism of muscle wasting, the physiologic and molecular basis for lysosomal glycogen metabolism and the exciting potential of using dietary, exercise and signal transduction regulation to reduce and/or reverse the muscle defects in Pompe's disease. In this proposal we will examine the mechanism(s) responsible for muscle degradation and the consequences of lysosomal alkalization on mTORC1 activation and macroautophagy. This information will then be used to design specific nutrition, exercise, pharmacologic, and hormonal signaling regulators to restore lysosome function and ameliorate the skeletal muscle degeneration that occurs in GAA deficiency.

Public Health Relevance

Pompe's disease is a relatively rare autosomal recessive inherited disease that results from mutations in the acid alpha-glucosidase (GAA) gene resulting in a reduced enzymatic activity with the massive accumulation of glycogen in lysosomes. Although these mutations occur throughout the body, the primary defect occurs in cardiac and skeletal muscle and depending upon the specific mutations and degree of GAA enzymatic activity results in a spectrum of phenotypes that include a rapid fatal infantile disorder, juvenil and a late-onset adult myopathy. The infantile onset form presents as hypotonia (muscle weakness) with massive accumulation of glycogen in skeletal and heart muscle, and death due to cardiorespiratory failure. In addition, the classical infantile-onset form also results in hepatomegaly due to increased glycogen deposition within the liver. Adult individuals with the slowly progressive form develop severe skeletal muscle weakness and eventually respiratory failure. Glycolytic type II muscle fibers (white muscle) are primarily affected in Pompe's disease whereas oxidative type I muscle fibers (red) are relatively spared. Recent studies have observed that pompe mice display defective skeletal muscle macroautophagy with the accumulation of autophagic vacuole intermediates. Macroautophagy is a complex process by which organelles (ie: mitochondria), macromolecules (ie: glycogen) and cytoplasmic components are entrapped into autophagosomes that fuse with the lysosome for breakdown and release of individual molecular components. The finding of defective macroautophagy glycolytic muscle of pompe mice raises several novel hypotheses critical with regard to the mechanism of muscle atrophy, the physiologic and molecular basis for glycogen transport into lysosomes and the exciting potential of using dietary, exercise and signal transduction regulation to reduce and/or reverse the muscle defects in Pompe's disease. Thus, this proposal is focused on elucidating the integrative and dynamic control of these pathways to understand the molecular basis for the pathophysiology that occurs during GAA deficiency and the basis for selective glycolytic skeletal muscle degeneration that does not occur in other genetic models of skeletal muscle macroautophagy inhibition.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
1R01AR064420-01
Application #
8481653
Study Section
Integrative Physiology of Obesity and Diabetes Study Section (IPOD)
Program Officer
Nuckolls, Glen H
Project Start
2013-03-07
Project End
2018-02-28
Budget Start
2013-03-07
Budget End
2014-02-28
Support Year
1
Fiscal Year
2013
Total Cost
$455,167
Indirect Cost
$182,612
Name
Albert Einstein College of Medicine
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
110521739
City
Bronx
State
NY
Country
United States
Zip Code
10461
Cao, Yanyan; Wang, Yichen; Abi Saab, Widian F et al. (2014) NRBF2 regulates macroautophagy as a component of Vps34 Complex I. Biochem J 461:315-22