Why are muscles unable to properly break down glycogen?

Why Muscles Cannot Properly Break Down Glycogen

Primary Enzymatic Deficiencies

Muscles are unable to properly break down glycogen due to inherited deficiencies in specific enzymes required for glycogenolysis and glycolysis, most commonly affecting the debranching enzyme (glycogen storage disease type III) or myophosphorylase (GSD type V). 1

Key Enzyme Defects

The complete degradation of muscle glycogen requires two critical enzymes working in tandem:

• Myophosphorylase cleaves the α-1,4-glycosidic bonds in the linear chains of glycogen 1
• Debranching enzyme (GDE) possesses dual catalytic activities on a single polypeptide: transferase activity and amylo-1,6-glucosidase (AGD) activity to remove branch points 1

When either enzyme is deficient, glycogen accumulates in abnormal forms with characteristic structural abnormalities—specifically, glycogen with short outer chains resembling phosphorylase-limit dextrin in debranching enzyme deficiency 1

Clinical Manifestations by Enzyme Type

Debranching Enzyme Deficiency (GSD III)

In GSD IIIa, the muscle manifestations differ markedly from other glycogenoses because glycogen branches accessible to myophosphorylase provide sufficient anaerobic glycogenolysis to prevent exercise-induced contractures and rhabdomyolysis. 1

Key clinical features include:

• Progressive weakness typically emerging in the 3rd or 4th decade of life, affecting both proximal muscles (hip extensors, abductors, abdominal muscles) and distal muscles with grip weakness 1
• Absence of dynamic exercise intolerance symptoms (no contractures or recurrent rhabdomyolysis) unlike GSD V and VII 1
• Childhood hypotonia with 80% of children showing gross motor function below the 25th percentile for age 1
• Variable cardiomyopathy with ventricular hypertrophy as a frequent finding 1

Myophosphorylase Deficiency (GSD V - McArdle Disease)

• Exercise intolerance with muscle contractures and recurrent rhabdomyolysis episodes 1, 2
• Second wind phenomenon during constant workload exercise 3
• Acute renal failure risk from myoglobinuria 2

Pathophysiologic Mechanisms

Energy Metabolism Disruption

Muscle glycogen serves as the crucial fuel for both anaerobic metabolism during maximal effort and as a substrate for oxidative phosphorylation during the transition from rest to exercise. 1

The metabolic consequences include:

• Limited anaerobic capacity due to inability to rapidly mobilize glucose from glycogen stores 1
• Impaired oxidative metabolism as glycogen is critical for supporting maximal rates of oxidative phosphorylation 1
• Compensatory mechanisms through increased utilization of alternative oxidative fuels (free fatty acids and ketone bodies) and enhanced gluconeogenesis capacity 1

Why GSD III Differs from Other Glycogenoses

The protective effect in GSD III occurs because:

• Retained myophosphorylase activity can still access the outer glycogen branches, providing some glycogenolytic capacity 1
• Hepatic glucose restriction limits sustained exercise but prevents the severe exercise-induced symptoms seen in phosphorylase deficiency 1
• Abundance of alternative fuels compensates for limited glycogen breakdown 1

Genetic Basis

The debranching enzyme gene (AGL) is located on chromosome 1p21, spans 85 kb with 35 exons, and encodes a 1532 amino acid protein with dual catalytic activities. 1

• Autosomal recessive inheritance affects multiple ethnic groups 1
• Type IIIa (85% of cases) involves both liver and muscle 1
• Type IIIb (15% of cases) affects only liver with preserved muscle debranching enzyme 1

Diagnostic Approach

Laboratory Findings

• Elevated serum creatine kinase (CK) in patients with muscle involvement, though normal CK does not exclude muscle enzyme deficiency 1
• Muscle biopsy shows abnormal glycogen deposits with characteristic short outer chains 1, 4
• Enzyme activity assays demonstrate markedly decreased debranching activity with normal phosphorylase activity 4

Critical Pitfall

Normal lactate response during ischemic forearm exercise can occur in some glycogenoses (like PHK deficiency), but lactate fails to rise appropriately during dynamic submaximal exercise, distinguishing these from normal metabolism. 3

Clinical Monitoring Requirements

For patients with muscle-affecting glycogenoses:

• Serial CK measurements to monitor disease progression 5
• Cardiac evaluation including ECG and echocardiography for ventricular hypertrophy 1
• Respiratory function monitoring even when limb weakness appears mild, due to risk of nocturnal hypoventilation 6
• Hepatic surveillance with liver enzymes, coagulation studies, and imaging every 6-12 months for GSD III patients 1