Myofiber-type-dependent 'boulder' or 'multitudinous pebble' formations across distinct amylopectinoses

Area of Science:

• Biochemistry
• Cell Biology
• Neuroscience

Background:

• Glycogen's spherical structure is crucial for its function.
• Deficiencies in enzymes like E3 ubiquitin ligases lead to amylopectinosis, causing severe neurological and neuromuscular diseases such as adult polyglucosan body disease (APBD), Lafora disease (LD), and type 1 polyglucosan body myopathy (PGBM1).
• The precise roles of these enzymes in glycogen structuring remain largely unknown.

Purpose of the Study:

• To investigate the functions of enzymes involved in glycogen structuring.
• To compare the mechanisms of amylopectinosis in APBD, LD, and PGBM1 using a murine model.
• To elucidate the factors influencing polyglucosan body formation and its pathological consequences.

Main Methods:

• Comparative murine study of APBD, LD, and PGBM1 models.
• Analysis of polyglucosan body formation in different skeletal muscle myofiber types.
• Investigation of the role of sex and specific enzymes (e.g., RBCK1) in amylopectinosis.
• Assessment of cell necrosis and ubiquitination pathways.

Main Results:

• Polyglucosan bodies in skeletal muscle form as 'pebbles' (small, numerous) in glycolytic fibers and 'boulders' (giant, single) in oxidative fibers.
• Oxidative myofibers exhibit relative protection against amylopectinosis, partly due to increased glycogen branching enzyme expression.
• Polyglucosan body size correlates with cell necrosis, and sex influences amylopectinosis in a genotype-, brain region-, and myofiber-type-specific manner.
• RBCK1 deficiency-associated amylopectinosis is not caused by loss of linear ubiquitination, suggesting alternative RBCK1/LUBAC functions in glycogen shaping.

Conclusions:

• Myofiber type is a primary determinant of polyglucosan body morphology.
• Oxidative muscle fibers possess protective mechanisms against glycogen storage disorders.
• RBCK1's role in glycogen structuring extends beyond its known function in linear ubiquitination.
• This research provides critical insights into the structural determinants of glycogen and its role in neurological and neuromuscular health and disease.