Glycogen Degradation

Glycogen Structure and Function

• Glycogen is a large, branched polymer of glucose residues, primarily linked by α(1→4) bonds, with branching occurring approximately every 12th glucose via α(1→6) bonds.
• It serves as a key energy source for runners due to its ability to be mobilized quickly.
• Only 2% of muscle mass contains glycogen; however, the liver has a 10% concentration.
• Glycogen keeps blood glucose levels stable between meals, especially important for brain function, as glucose is a primary fuel for the brain.

Glycogen Breakdown Requires Several Enzymes

• Efficient glycogen breakdown involves four key enzymatic activities:
  • Glycogen phosphorylase: Degrades glycogen to form glucose 1-phosphate.
  • Debranching enzyme: Converts branched structures to linear ones to facilitate further breakdown.
  • Transferase: Moves glucosyl residues within the glycogen molecule.
  • Phosphoglucomutase: Converts glucose 1-phosphate to glucose 6-phosphate.

Glycogen Phosphorylase Mechanism

• Glycogen phosphorylase cleaves glycosidic bonds via phosphorolysis, yielding glucose 1-phosphate.
• This reaction is energetically favorable since glucose 1-phosphate is already phosphorylated, eliminating the need for ATP consumption.

Limitations of Glycogen Phosphorylase

• Cannot cleave α(1→6) bonds at branch points; therefore, other enzymes are required to manage these branches.
• The debranching enzyme hydrolyzes these bonds releasing free glucose.

Regulation of Glycogen Breakdown

• Allosteric Regulation and Phosphorylation: Glycogen phosphorylase is modulated by:
  • Allosteric effectors reflecting the energy state of the cell (e.g., AMP, ATP).
  • Reversible phosphorylation primarily in response to glucagon and epinephrine.
• Two isozymes exist:
  • Liver phosphorylase (phosphorylase a): Default is active form; inhibited by glucose.
  • Muscle phosphorylase (phosphorylase b): Default is inactive; activated in response to AMP during muscle contraction.

Enzyme Activation Pathways

• Protein kinase A activation: Triggered by glucagon and epinephrine through a G-protein-coupled pathway leading to the activation of phosphorylase kinase.
• Elevated cAMP levels lead to rapid mobilization of glucose from glycogen stores.

Hormonal Control of Glycogen Breakdown

• Epinephrine: Primarily stimulates glycogen breakdown in muscle for immediate energy needs during exertion.
• Glucagon: Signals the liver to release glucose when energy availability is low (e.g., during fasting).
• Both hormones bind to 7TM receptors, activating a signal cascade that amplifies responses for rapid glucose release.

Glycogen Depletion and Fatigue

• Depletion of glycogen stores correlates with onset of fatigue, known as "hitting the wall".
• Studies indicate that metabolic products like ADP may be more directly linked to fatigue than glycogen depletion itself.

Clinical Implications of Glycogen Breakdown Disorders

• Hers Disease: Deficiency in liver glycogen phosphorylase, leading to glycogen accumulation, hepatomegaly, and hypoglycemia. Variable symptoms among patients.
• McArdle's Disease: Caused by a lack of skeletal muscle glycogen phosphorylase; leads to exercise-induced muscle pain and rhabdomyolysis.

Biochemical Profiles of Muscle Fiber Types

• Type I (slow-twitch): Energy from fatty acids; low glycogen phosphorylase activity.
• Type IIb (fast-twitch): High glycogen and phosphorylase activity; utilizes glucose quickly for bursts of power.
• Type IIa fibers: Intermediate features; can adapt to training for oxidative or glycolytic performance.

Conclusion

• Glycogen metabolism is intricately regulated by hormonal signals, cellular energy states, and specific enzyme activities, playing a crucial role in energy management during physical activity, and its malfunction can lead to significant metabolic diseases.