Fuels for Muscle Contraction

• Muscle is the major biochemical transducer, it converts potential (chemical) energy into kinetic (mechanical) energy.
• For effective chemical-mechanical transduction, a constant supply of chemical energy is required via ATP.
• Magnitude and duration of exercise and the major fibers involved influences the primary fuel used to support muscle contraction.
• Muscle contraction and exercise relies on the breakdown of ATP, releasing free energy.
• This free energy is coupled to the energy requirements for muscle contraction: ATP becomes ADP + Pi + energy which fuels muscle contraction.
• The total amount of ATP stored in the body's cells is small, approximately 8 mmol/kg.
• This amount of ATP is sufficient for contraction for a maximum of 4 seconds.
• Due to the small stores of ATP, muscles rely on replenishing the ATP supply.

Sequential Use of Fuels

• ATP stores deplete in the first 4 seconds of exercise
• Then, ATP is regenerated by direct phosphorylation using creatine phosphate, lasting for 10 seconds.
• Next, anaerobic glycolysis from blood glucose, or mostly from muscle glycogen, provides ATP for 1-2 minutes.
• For prolonged exercise lasting hours, ATP is regenerated via the aerobic pathway using FFA & glucose as fuels.
• The anaerobic pathway occurs in the cytosol.
• The aerobic pathway occurs in the mitochondria.

Mechanisms to Replenish ATP in Muscle

• ATP phosphocreatine system (Phosphagen, direct phosphorylation, anaerobic).
• Glycolytic System (glycogen/lactate system, anaerobic).
• Oxidative phosphorylation (fatty acid, aerobic glycolysis).

ATP-CP Energy System

• This system uses creatine phosphate to regenerate ATP.
• Muscle cells store enough ATP to maintain activity for 1 to 3 seconds.
• CP (4 to 6 times ATP) is broken down to regenerate ATP as more energy is needed.
• The ATP-CP system is an anaerobic reaction, occurring in the absence of oxygen.
• CP is used during intense, short bursts of activity: lifting, jumping, sprinting.
• Stores of ATP and CP can support maximal physical effort for about 3 to 15 seconds.
• Carbohydrate and Fat are needed to support activities of longer duration.

Metabolism of Creatine Phosphate Anabolism (Synthesis)

• Creatine phosphate is found in muscle.
• It is a high-energy compound which maintains intracellular ATP levels during intense muscle exercise in the first few seconds.
• This system dominates during quick bursts such as the 100 m dash or lifting weights, dominating in the first few seconds.
• Creatine phosphate is a high energy compound, found in muscle.
• Synthesis starts in the kidney, continues in the liver, and ends in the muscle (where it is stored).
• Creatine phosphate synthesis depends on healthy kidney and liver function.
• The creatine phosphate amount depends on muscle mass.
• Creatine phosphate is synthesized from the amino acids: glycine, arginine (guanido group of arginine), and methionine (as a methyl group donor).
• After creatine is synthesized in the liver, it diffuses to the blood.
• Creatine is taken up and stored by skeletal muscle, the heart, and the brain.
• Creatine is reversibly phosphorylated in such organs and remains there to maintain cellular ATP levels when needed, by phosphorylating ADP to form ATP.

Fate of Creatine

• Creatinine is constantly synthesized from the breakdown of creatine and creatine phosphate.
• Creatinine diffuses out from muscle to blood, then is excreted from the kidney in the urine.
• Creatinine level in urine in normal individuals is constant.
• Creatinine level in blood and urine is directly proportionate to total creatine phosphate content, which is correlated to muscle mass.
• Creatinine level can indicate muscle mass.
• Since creatinine is constantly synthesized and is only excreted by the kidney, plasma creatinine level can indicate kidney function.
• Elevated creatinine levels in plasma indicate impaired kidney function.
• The level of creatinine decreases in blood and urine in conditions of muscle dystrophy (paralysis or muscle atrophy).
• Normal serum creatinine:
  • 0.6 to 1.2 mg/dL average in adult males.
  • 0.5 to 1.1 mg/dL average in adult females.

CK Isoenzymes

• CK has three isoenzymes:
  • CK-MM (mainly in skeletal muscle).
  • CK-MB (mainly in the heart muscle).
  • CK-BB (mainly in the brain).
• Serum total CK increases with damage of skeletal or cardiac muscles.
• Myocardial infarction is a type of damage to the heart.

Glycolytic System and Glycogen Metabolism

• Glycogenesis is the synthesis of glycogen to store excess glucose in less space.
• Glycogenesis is effectively an elongation to a glycogen primer.
• The process of glycogenesis occurs in the cytoplasm of the liver and muscle.
• The first step of glycogenesis is the preparation of a substrate which is used in the next step: elongation.
• A substrate is prepared using glycogen primer and UDP glucose.
• Glycogen primer is a stretch of 4-6 molecules of glucose residues linked by a 1,4 glycosidic linkage.
• Glycogen primer is needed, as the glycogen synthase enzyme responsible for glycogen synthesis can not initiate chain synthesis using glucose as an acceptor of a glucose molecule from UDP glucose.
• A fragment of stored glycogen acts as a glycogen primer, but glycogenin protein can act as glycogen primer if glycogen depleted.
• Glycogenin has enzyme activity: it catalyzes glucose transfer from UDP-glucose, forming a short linked glucosyl chain that will act as a primer for glycogen synthesis.

Synthesis of UDP Glucose

• Glucose is first converted to glucose 6 phosphate.
• Glucose 6 phosphate is converted to glucose 1 phosphate.
• Glucose 1 phosphate reacts with UTP.
• The result is UDP-glucose and pyrophosphate (P~P).
• The last enzyme used is UDP-glucose pyrophosphorylase, also known as glucose 1 phosphate uridyl transferase.

Elongation of Glycogen Chain

• Elongation of glycogen chain (or glycogen primer) is catalyzed by glycogen synthase and branching enzymes.
• Glycogen synthase catalyzes the formation of a 1,4 glycosidic bond by the transfer glucose from UDP-glucose to the glycogen primer.
• Branching enzyme catalyzes glucose transfer of 4-6 molecules in block from 1,4 to 1,6 glycosidic bond (1,4-1,6 glucosyl transferase activity), establishing a branch point.
• Glycogenesis works to maintain blood glucose level in early starvation.
• Glycogen storage stores excess glucose in less space by decreasing the osmotic effect of glucose.

Glycogenolysis

• Glycogen is broken down by Glycogen phosphorylase.
• α(14) →α(1→4)-glucan transferase breaks down Glycogen phosphorylase.
• Glucose, is broken down by Amylo-α(1→6)-glucosidase.
• The product of the above reaction is Glucose 1-phosphate.
• Glucose 1-phosphate is broken down by Phosphoglucomutase.
• In muscle, Glucose 6-phosphate is the last step.
• Glucose 6-phosphatase is a final step in the Liver.

Glycogenolysis in Muscles

• Lack of glucose-6-phosphatase enzyme, it ends with glucose 6 phosphate.
• This then supplies energy, utilized for muscle contraction.

Glycogenolysis in the Liver

• Due to presence of glucose 6 phosphatase enzyme, glucose 6 phosphate is converted to free glucose to maintain blood glucose level during early starvation.

Hormonal Regulation of Glycogenesis

• The key regulatory enzyme of glycogenesis is glycogen synthase.
• The enzyme can present in one of two forms. Glycogen synthase a, is active or dephosphorylated form. Glycogen synthase b is inactive or phosphorylated form.
• Glycogen synthase is covalently activated by insulin, as it is active in its dephosphorylated form.
• Glycogen synthase is covalently inhibited by glucagon (in the liver only), and epinephrine (in the liver and muscle), which makes it inactive in the phosphorylated form.

Allosteric Regulation of Glycogenesis

• Glucose 6 phosphate and ATP allosterically activate glycogen synthase a, thus activating glycogenesis.
• Glycogen and ADP, also AMP, allosterically inhibit glycogen synthase a, thus inhibiting glycogenesis.

Allosteric Regulation of Glycogenolysis

• Glucose 6 phosphate and ATP allosterically inhibit glycogen phosphorylase a which inhibits glycogenolysis.
• Increased intracellular Ca leads to binding of Ca to calmodulin forming Ca-calmodulin complex.
• The Ca-calmodulin complex allosterically activates phosphorylase kinase, which in turn activate glycogen phosphorylase.

Hormonal Regulation of Glycogenolysis

• The key regulatory enzyme is glycogen phosphorylase.
• Glycogen phosphorylase can present in one of two forms: active form (phosphorylated; or a-form), inactive form (dephosphorylated; or b-form).
• Glycogen phosphorylase is covalently inhibited by insulin; glycogen phosphorylase is inactive in dephosphorylated form.
• Glycogen phosphorylase is covalently activated by glucagon in the liver and epinephrine in both the liver and muscle; glycogen phosphorylase is active in phosphorylated form.

Inborn Errors of Glycogen Metabolism (Glycogen Storage Diseases)

• These are a group of inborn errors of metabolism affecting glycogen metabolism.

Types of Glycogen Storage Diseases:

• Type I (Von Gierck's disease): Deficiency of glucose 6 phosphatase causing fasting hypoglycemia and hepatomegaly with increased hepatic content of glycogen and TAG.
• Type II (Pomp's disease): Deficiency of lysosomal acid maltase, which is lethal with early death.
• Type III (Cori disease): Deficiency of debranching enzyme, resulting in myopathy.
• Type IV (Anderson disease): Deficiency of branching enzyme, causing failure to thrive.
• Type V (Mac Ardle disease): Deficiency of muscle glycogen phosphorylase, resulting in myopathy.
• Type VI (Hers' disease): Deficiency of hepatic glycogen phosphorylase, leading to fasting hypoglycemia and hepatomegaly with increased hepatic content of glycogen and TAG.