Muscle Energetics and Creatine Metabolism

Regulation of Energy Metabolism

• This presentation covers the regulation of energy metabolism, focusing on creatinine, creatinine phosphate, and glycogen.

Subtopics

• The brain and energy metabolism
• Glucagon and insulin
• Creatinine phosphate
• Creatinine
• Glycogen
• Gluconeogenesis
• Fructose
• Fatty acids
• The Krebs cycles
• Fermentative and aerobic metabolism

Creatine Phosphate

• Creatine phosphate (CP) or PCr, also known as phosphocreatine, is a phosphorylated creatine molecule.
• It acts as a rapidly mobilizable reserve of high-energy phosphates in skeletal muscle and brain.
• This allows recycling of adenosine triphosphate (ATP), the energy currency of the cell.
• The chemical structure of creatine phosphate is shown.
• In the kidneys, the enzyme AGAT converts arginine and glycine into guanidinoacetate (GAA).
• A methyl group is added to GAA from methionine by the enzyme GAMT, forming unphosphorylated creatine.
• Creatine is transported to the liver, where it is phosphorylated into creatine phosphate.
• Released into the blood, it travels mainly to muscle cells (95%), brain, heart, and pancreas.

Chemistry of Creatine Phosphate

• Inside cells, the enzyme complex creatine kinase transforms creatine into phosphocreatine.
• The enzyme facilitates the transfer of the phosphate group to convert ADP into ATP
• This process is pivotal for all vertebrates' bioenergetic systems.
• A 70kg person generally has around 120g of creatine, with 40% unphosphorylated and 60% as creatine phosphate.
• Around 1-2% of this is broken down and excreted as creatinine daily.
• Phosphocreatine is additionally used intravenously in hospitals (as Neoton) for cardiovascular problems. This is not a controlled substance.
• Creatine phosphate can be broken down into creatinine, which is excreted in the urine.

Functions of Creatine Phosphate

• Phosphocreatine anaerobically donates a phosphate group to ADP to generate ATP during intense muscular or neuronal activity, within 2 to 7 seconds.
• Excess ATP is used during low-effort periods to convert creatine to phosphocreatine, the reversible reaction catalyzed by creatine kinases.
• Creatine kinase (CK-MB) presence in blood plasma indicates tissue damage, specifically useful for diagnosing myocardial infarction.
• The cell's ability to generate phosphocreatine from excess ATP during rest and its use during intense activity creates a spatial and temporal buffer of ATP concentration.

Creatinine

• Creatinine is a breakdown product of creatine phosphate in muscle.
• Creatinine is cleared from the body through urine.
• Its production rate is mostly consistent, depending on muscle mass.
• The chemical structure of creatinine is shown.

Physiology of Creatinine

• Creatinine is produced via a biological system involving creatine, creatine phosphate, and ATP.
• Creatine is also synthesized primarily in the liver from methylation of glycocyamine by S-adenosyl methionine.
• Creatinine travels through the blood to other organs, muscle, and brain, becoming high energy compound creatine phosphate through phosphorylation.
• Creatinine is removed from the blood principally by the kidneys through glomerular filtration.
• Little or no tubular reabsorption of creatinine occurs.
• Kidney filtration deficiency leads to escalating blood creatinine concentrations.

Diagnostic Use of Creatinine

• Serum creatinine is a standard indicator of renal function (although not a direct measure).
• Elevated creatinine may not always signify decreased GFR or real kidney impairment; it could be due to increased production, interference in testing, or reduced tubular secretion.
• Blood creatinine levels are used to calculate creatinine clearance (CrCl), which approximates the glomerular filtration rate (GFR).
• eGFR (estimated GFR) can be calculated using blood creatinine levels alone.

Glycogen

• Glycogen is a multi-branched polysaccharide of glucose that's a primary form of energy storage in the body.
• It's one of two types of long-term energy reserves, the other being triglycerides in adipose tissue.

Structure of Glycogen

• Glycogen is a branched biopolymer of glucose residues.
• Chains are generally 8-12 glucose units long.
• Glucose units are connected linearly with α(1→4) glycosidic bonds.
• Branches are attached to the chains with α(1→6) glycosidic bonds.
• A glycogenin protein forms the core of the glycogen granule.

Function of Glycogen

• Glycogen serves as a readily available energy source, especially during intense muscular or brain activity.
• Muscle glycogen provides immediate energy for muscle cells.
• Liver glycogen serves as a store of glucose for the body, including the central nervous system.

Glycogen Metabolism

• Glycogen degradation involves three steps: releasing glucose 1-phosphate from glycogen, remodeling for further breakdown, and converting glucose 1-phosphate to glucose 6-phosphate for metabolism.
• Glucose 6-phosphate has three possible fates: glycolysis, pentose phosphate pathway, or conversion to free glucose and release into the bloodstream (mostly in the liver).
• Glycogen synthesis requires UDP-glucose which is composed of UTP and glucose 1-phosphate.
• UDP-glucose is added to nonreducing end of glycogen molecules.
• Glycogen metabolism is complex, regulated allosterically by metabolites signalling cellular energy needs and hormonally stimulated cascades, altering the enzymes kinetic properties.