1. Energy Use and the Level of Muscle Activity

3. GLYCOGENOLYSIS PATHWAYS
glycogensis -
glycogenolysis
1. Glucagons – pancreas – low glucose level
2. Epinephrine – adrenal Glands of kidney - stress
HORMONE +

4. GLYCOGENOLYSIS
In glycogenolysis, glycogen stored in the liver and muscles, is converted first to glucose-1- phosphate and then into glucose-6-phosphate. Two hormones which control glycogenolysis are a peptide, glucagon from the pancreas and epinephrine from the adrenal glands.
Glucagon is released from the pancreas in response to low blood glucose and epinephrine is released in response to a threat or stress. Both hormones act upon enzymes to stimulate glycogen phosphorylase to begin glycogenolysis and inhibit glycogen synthetase (to stop glycogenesis).

5. Glycogen is a highly branched polymeric structure containing glucose as the basic monomer. First individual glucose molecules are hydrolyzed from the chain, followed by the addition of a phosphate group at C-1. In the next step the phosphate is moved to the C-6 position to give glucose 6-phosphate, a cross road compound.
Glucose-6-phosphate is the first step of the glycolysis pathway if glycogen is the carbohydrate source and further energy is needed. If energy is not immediately needed, the glucose-6-phosphate is converted to glucose for distribution in the blood to various cells such as brain cells.

6. Glycogenolysis and the fate of glycogen in liver
LIVER PATHWAY
Glycogen Pi
glycogen
phosphorylase
Glucose-1-phosphate
phosphoglucomutase
glucose-6-phosphatase
Glucose-6-phosphate
Glucose Pi
PYRUVIC ACID
glucose
Glucose 6 phosphate
LACTIC ACID
glycogen
Glycogenolysis and the fate of glycogen in liver

7. Glycogenolysis and the fate of glycogen in musclePi
MUSCLE PATHWAY
glycogen
phosphorylase
Glucose-1-phosphate
phosphoglucomutase
Glucose-6-phosphate
glycolysis
lactate dehydrogenase
Lactate
Anaerobic glycolysis
Pyruvate
pyruvate
dehydrogenase
Acetyl CoA
CO2
Aerobic metabolism
Glycogenolysis and the fate of glycogen in muscle

9. The sequence of epinephrine stimulating events is outlined as follows:
Epinephrine binds to a receptor on the muscle cell membrane and stimulates adenyl cyclase in the membrane.
2) Adenyl cyclase in the membrane catalyzes the formation of cyclic AMP from ATP.
3) The increase of cyclic AMP activates a protein kinase. The binding of cyclic AMP to an enzyme is an allosteric control where the enzyme is "switched on" for activity.
4) The protein kinase causes phosphorylations (addition of phosphate) on a series of phosphorylation enzymes which activates them to finally produce glucose-1-phosphate.
4a) At the same time that enzymes are being activated for glycogen breakdown, glycogen synthetase enzyme must be inactivated. Glycogenesis must be "switched off" and glycogenolysis "switched on.“
5) Glucose-6-phosphate is the final result of the initial stimulation by epinephrine or other hormones such as glucagon. If this happened to a muscle cell, then the glycolysis pathway is the next step in the sequence. If this happened to a liver cell stimulated by glucagon, then glucose is produced to enter the blood stream.

10. Regulation of glycogen phosphorylaseOH
relaxed
active
+G-6-P
+ATP
(in muscle)
+AMP
activation by calcium
inhibition by glucose-6-P Pi
protein
phosphatase-1
tense-
inactive
phosphorylase-b
ATP
ADP
phosphorylase
kinase
phosphorylase-a
OPO3
Regulation of glycogen phosphorylase

11. Regulation of glycogen synthase
ATP
ADP
variety of
protein kinases
active
Glycogen
synthase-i OH
inactive
OPO3
Glycogen
synthase-d
+glucose-6-P
active
enzyme Pi
protein phosphatase
Regulation of glycogen synthase

12. MUSCLES AND EXERCISE
CAMNE YE???
HOW????

13. Resting skeletal muscle
A resting muscle breaks down fatty acids by aerobic metabolism to make ATP. Surplus ATP is used to build reserves of creatine phosphate (CP) and glycogen
In a resting skeletal muscle, the demand for ATP is low. More than enough oxygen is available for the mitochondria to meet that demand, and they produce a surplus of ATP. The extra ATP is used to build up reserves of CP and glycogen. Resting muscle fibers absorb fatty acids and glucose that are delivered by the bloodstream. The fatty acids are broken down in the mitochondria, and the ATP generated is used to convert creatine to creatine phosphate (CP) and glucose to glycogen.

14. Muscle at moderate level of activities
At modest activity levels, mitochondria can meet the ATP demands through the aerobic metabolism of fatty acids and glucose
At moderate levels of activity, the demand for ATP increases. This demand is met by the mitochondria. As the rate of mitochondrial ATP production rises, so does the rate of oxygen consumption. Oxygen availability is not a limiting factor, because oxygen can diffuse into the muscle fiber fast enough to meet mitochondrial needs. But all the ATP produced is needed by the muscle fiber, and no surplus is available. The skeletal muscle now relies primarily on the aerobic metabolism of pyruvic acid to generate ATP. The pyruvic acid is provided by glycolysis, which breaks down glucose molecules obtained from glycogen in the muscle fiber. If glycogen reserves are low, the muscle fiber can also break down other substrates, such as lipids or amino acids. As long as the demand for ATP can be met by mitochondrial activity, the ATP provided by glycolysis makes a relatively minor contribution to the total energy budget of the muscle fiber.

15. Muscle at peak levels of activity
At peak activity levels, mitochondria cannot get enough oxygen to meet ATP demands. Most of the ATP is provided by glycolysis, leading to the production of lactic acid.
Mitochondria cannot produce more of the required ATP – so ATP was produced by other pathways
At peak levels of activity, the ATP demands are enormous and mitochondrial ATP production rises to a maximum. This maximum rate is determined by the availability of oxygen, and oxygen cannot diffuse into the muscle fiber fast enough to enable the mitochondria to produce the required ATP. At peak levels of exertion, mitochondrial activity can provide only about one-third of the ATP needed. The remainder is produced through glycolysis

16. When glycolysis produces pyruvic acid faster than it can be utilized by the mitochondria, pyruvic acid levels rise in the sarcoplasm. Under these conditions, pyruvic acid is converted to lactic acid, a related three-carbon molecule
The anaerobic process of glycolysis enables the cell to generate additional ATP when the mitochondria are unable to meet the current energy demands. However, anaerobic energy production has its drawbacks:
Lactic acid is an organic acid that in body fluids dissociates into a hydrogen ion and a negatively charged lactate ion. The production of lactic acid can therefore lower the intracellular pH. Buffers in the sarcoplasm can resist pH shifts, but these defenses are limited. Eventually, changes in pH will alter the functional characteristics of key enzymes. The muscle fiber then cannot continue to contract.
Glycolysis is a relatively inefficient way to generate ATP. Under anaerobic conditions, each glucose molecule generates 2 pyruvic acid molecules, which are converted to lactic acid. In return, the cell gains 2 ATP through glycolysis. Had those 2 pyruvic acid molecules been catabolized aerobically in a mitochondrion, the cell would have gained 34 additional ATP??????

17. Normal Muscle – resting stage
Normal muscle function requires
(1) substantial intracellular energy reserves,
(2) a normal circulatory supply, and
(3) a normal blood oxygen concentration.
Anything that interferes with one or more of those factors will promote premature muscle fatigue.
For example, reduced blood flow from tight clothing, a circulatory disorder, or loss of blood slows the delivery of oxygen and nutrients, accelerates the buildup of lactic acid, and promotes muscle fatigue.

18. Muscle at moderate level of activities
If the muscle fiber is contracting at moderate levels and ATP demands can be met through aerobic metabolism, fatigue will not occur until glycogen, lipid, and amino acid reserves are depleted. This type of fatigue affects the muscles of long-distance athletes, such as marathon runners, after hours of exertion.
When a muscle produces a sudden, intense burst of activity at peak levels, most of the ATP is provided by glycolysis. After just seconds to minutes, the rising lactic acid levels lower the tissue pH, and the muscle can no longer function normally. Athletes who run sprints, such as the 100-meter dash, get this type of muscle fatigue.

19. Muscle Fatigue – higher level of activities
A skeletal muscle fiber is said to be fatigued when it can no longer contract despite continued neural stimulation (walaupun sorakan kuat diberikan)
The cause of muscle fatigue varies with the level of muscle activity. After short peak levels of activity, such as running a 100-meter dash, fatigue may result from the exhaustion of ATP and CP reserves or from the drop in pH that accompanies the buildup of lactic acid.

20. After prolonged exertion, such as running a marathon, fatigue may involve physical damage to the sarcoplasmic reticulum that interferes with the regulation of intracellular Ca2+ concentrations.
Muscle fatigue is cumulative -- the effects become more pronounced as more muscle fibers are affected. The result is a gradual reduction in the capabilities of the entire skeletal muscle.

21. The Recovery Period
When a muscle fiber contracts, the conditions in the sarcoplasm are changed. Energy reserves are consumed, heat is released, and, if the contraction was at peak levels, lactic acid is generated.
In the recovery period, the conditions in muscle fibers are returned to normal, preexertion levels. It may take several hours for muscle fibers to recover from a period of moderate activity. After sustained activity at higher levels, complete recovery can take a week.

22. Lactic Acid Removal and Recycling
Glycolysis enables a skeletal muscle to continue contracting even when mitochondrial activity is limited by the availability of oxygen. As we have seen, however, lactic acid production is not an ideal way to generate ATP. It squanders the glucose reserves of the muscle fibers, and it is potentially dangerous because lactic acid can alter the pH of the blood and tissues.
During the recovery period, when oxygen is available in abundance, that lactic acid can be recycled by conversion back to pyruvic acid. The pyruvic acid can then be used either by mitochondria to generate ATP or as a substrate for enzyme pathways that synthesize glucose and rebuild glycogen reserves.

23. During a period of exertion (active exercises), lactic acid diffuses out of the muscle fibers and into the bloodstream. This process continues after the exertion has ended, because intracellular lactic acid concentrations are still relatively high. The liver absorbs the lactic acid and converts it to pyruvic acid.
Roughly 30 percent of these pyruvic acid molecules are broken down in the TCA cycle, providing the ATP needed to convert the other pyruvic acid molecules to glucose. The glucose molecules are then released into the circulation, where they are absorbed by skeletal muscle fibers and used to rebuild their glycogen reserves. This shuffling of lactic acid to the liver and glucose back to muscle cells is called the Cori cycle.

24. CORI CYCLE ???

25. MUSCULAR ACTIVITY AND THE CORI CYCLE
Muscular activity or its anticipation leads to the release of epinephrine by the adrenal medulla (kidney)
Epinephrine markedly stimulates glycogen breakdown (glycogenolysis) in muscles and, to a lesser extent, in the liver
Muscular activity quickly uses stored ATP as the energy source and more ATP must be generated by the breakdown of glycogen.

26. The Oxygen Debt
During the recovery period, oxygen is readily available and the body's oxygen demand remains elevated above normal resting levels. The recovery period is powered by the ATP that aerobic metabolism generates.
The more ATP required, the more oxygen will be needed. The oxygen debt, or excess post exercise oxygen consumption (EPOC), created during exercise is the amount of oxygen needed to restore normal, pre-exertion conditions.
Skeletal muscle fibers, which must restore ATP, creatine phosphate, and glycogen concentrations to their former levels, and liver cells, which generate the ATP needed to convert excess lactic acid to glucose, are responsible for most of the additional oxygen consumption.

27. However, several other tissues also increase their rate of oxygen consumption and ATP generation during the recovery period.
For example, sweat glands increase their secretary activity until normal body temperature is restored. While the oxygen debt is being repaid, the breathing rate and depth are increased. As a result, you continue to breathe heavily long after you stop exercising.

28. Heat Loss
Muscular activity generates substantial amounts of heat. When a catabolic reaction occurs, such as the breakdown of glycogen or the reactions of glycolysis, the muscle fiber captures only a portion of the released energy. The rest is released as heat.
A resting muscle fiber relying on aerobic metabolism captures about 42 percent of the energy released in catabolism. The other 58 percent warms the sarcoplasm, interstitial fluid, and circulating blood. Active skeletal muscles release roughly 85 percent of the heat needed to maintain normal body temperature.

29. When muscles become active, their consumption of energy skyrockets (INCREASE). As anaerobic energy production becomes the primary method of ATP generation, muscle fibers become less efficient at capturing energy.
At peak levels of exertion, only about 30 percent of the released energy is captured as ATP; the remaining 70 percent warms the muscle and surrounding tissues. Body temperature soon climbs, and heat loss at the skin accelerates through VARIOUS mechanisms.

30. Hormones and Muscle Metabolism
Metabolic activities in skeletal muscle fibers are adjusted by hormones of the endocrine system.
Growth hormone from the pituitary gland and testosterone (the primary sex hormone in males) stimulate the synthesis of contractile proteins and the enlargement of skeletal muscles.
Thyroid hormones elevate the rate of energy consumption by resting and active skeletal muscles. During a sudden crisis, hormones of the adrenal gland, notably epinephrine (adrenaline), stimulate muscle metabolism and increase both the duration of stimulation and the force of contraction.

31. Questions to be answered !!!
“ During intense activity, Nicol David one of the top ranking squash player in the world felt difficult in breathing. The Red Crescent paramedics gave an oxygen supply so that she could breathe easily. However, they did not realize the metabolism involved in her own body”.
Briefly describe the metabolic pathways involved during resting, moderate and intense activities that the athlete try to cope with her situation. Is there any relation with the CORI cycle?