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Bioenergetics and Exercising Muscle - Part 2

Bioenergetics and Exercising Muscle - Part 2

Overview of Energy Systems

  • The energy systems are intricately linked and continuously supply adenosine triphosphate (ATP) to meet cellular energy demands, particularly during physical activity.

  • They are categorized based on their requirement for oxygen:

    • Aerobic Energy Systems (cont.)

      • These systems are highly efficient, producing a large amount of ATP through the complete oxidation of fuel sources like carbohydrates, fats, and sometimes proteins.

      • The main pathway is oxidative phosphorylation, which relies on the presence of oxygen.

    • Other Fuel Sources

      • Beyond glucose, the body utilizes free fatty acids (FFAs) from triglycerides and, to a lesser extent, amino acids from proteins as fuel, especially during prolonged exercise or caloric restriction.

    • Interaction of Energy Systems

      • No single energy system operates in isolation; they all contribute simultaneously, but their relative contribution shifts based on the intensity and duration of exercise.

      • For example, high-intensity, short-duration activities heavily rely on anaerobic systems, while endurance activities primarily depend on aerobic systems.

    • Oxidative Capacity of Muscle

      • This refers to the muscle's maximal ability to consume oxygen and generate ATP aerobically.

      • It is influenced by factors such as:

        • Mitochondrial density and size: More mitochondria mean greater capacity for aerobic metabolism.

        • Activity of oxidative enzymes: Enzymes like citrate synthase and succinate dehydrogenase are key for the Krebs cycle and ETC.

        • Capillary density: A richer blood supply facilitates oxygen and nutrient delivery, and waste removal.

Review of Previous Concepts

  • ATP-PCr system:

    • Provides rapid, immediate energy for approximately 10−1510−15 seconds of maximal effort (e.g., short sprints, heavy lifting).

    • It regenerates ATP by transferring a phosphate group from phosphocreatine (PCr) to adenosine diphosphate (ADP), catalyzed by creatine kinase.

  • In anaerobic glycolysis:

    • Glucose or glycogen is broken down into pyruvate without oxygen.

    • If oxygen is not available in sufficient quantities (e.g., during high-intensity exercise) or mitochondria are not readily accessible, pyruvate is converted to lactate by lactate dehydrogenase (LDH).

    • This conversion is crucial because it regenerates nicotinamide adenine dinucleotide (NAD+), which is required for glycolysis to continue producing a small amount of ATP.

  • The final net amount of ATP produced from the complete aerobic oxidation of 11 molecule of glucose is typically 3232 ATP.

  • Starting with 11 molecule of glycogen yields 3333 ATP because the initial phosphorylation step of glucose (using 11 ATP) is bypassed when glycogen is the substrate.

  • When pyruvate successfully enters the mitochondria (in the presence of oxygen):

    • It undergoes oxidative decarboxylation and is converted to Acetyl-CoA by the pyruvate dehydrogenase complex.

    • This bridge step produces 11 NADH+ and releases 11 CO2O2​ per pyruvate molecule.

  • From 11 Acetyl-CoA, we initiate 11 turn of the Krebs cycle (also known as the citric acid cycle), which operates within the mitochondrial matrix.

  • The products after 11 turn of the Krebs Cycle (from one Acetyl-CoA) are:

    • 11 ATP (often generated as 11 GTP, which is readily converted to ATP).

    • 33 NADH+.

    • 11 FADH2.

    • 22 CO2O2​, which are released as metabolic waste.

Oxidative Phosphorylation – Phase 3 (Electron Transport Chain - ETC)

  • Role of H++ and Electrons (e−−):

    • H++ (protons) and electrons (e−−) are the key components brought to the ETC, primarily via the reduced coenzymes NADH+ and FADH2. These carriers are generated from glycolysis, pyruvate oxidation, the Krebs cycle, and eta -oxidation.

    • NADH+ and FADH2 donate their electrons to specific protein complexes embedded in the inner mitochondrial membrane, initiating the electron flow.

    • An excessive accumulation of H++ in the cytoplasm and mitochondrial matrix can create an acidic environment, disrupting enzyme function and cellular homeostasis.

    • Electrons travel sequentially down a chain of four protein complexes (Complexes I, II, III, and IV) and two mobile carriers (Ubiquinone and Cytochrome c), passing from higher to lower energy states.

    • The energy released during this electron transport is used to pump H++ ions.

    • The ETC ultimately creates ATP through chemiosmosis and produces H2O by combining H++ ions with oxygen, thereby providing energy and preventing the harmful buildup of H++ ions, which helps maintain pH balance.

  • ATP Synthesis Mechanism:

    • The energy derived from the flow of electrons down the ETC is utilized to actively pump H++ ions from the mitochondrial matrix into the intermembrane space, creating a high concentration gradient of H++ in this space.

    • This establishes an electrochemical potential energy difference, known as the proton motive force.

    • The subsequent movement of H++ ions back into the mitochondrial matrix, down their concentration gradient, occurs through a specialized protein complex called ATP synthase. This enzyme channel facilitates the inward flow of protons.

    • The H++ movement through ATP synthase triggers its rotational catalysis, which directly catalyzes the formation of ATP from ADP and inorganic phosphate (Pi).

    • In the mitochondrial matrix, the H++ ions that have passed through ATP synthase, along with electrons from the ETC, combine with molecular O2 to form H2O.

    • O2 serves as the final electron acceptor in the ETC. Without oxygen, the electron flow would cease, the proton gradient would dissipate, and aerobic ATP synthesis would halt.

  • ETC Complexes and Proton Pumping:

    • The ETC consists of 44 major protein complexes (Complexes I, II, III, and IV) and two mobile electron carriers located within the inner mitochondrial membrane.

    • 33 of these complexes (Complexes 11, 33, and 44) actively pump H++ from the mitochondrial matrix into the intermembrane space, contributing to the proton gradient:

      • Complex 11 (NADH dehydrogenase): Accepts electrons from NADH+ and pumps 44 H++.

      • Complex 33 (Cytochrome bc1 complex): Accepts electrons from Ubiquinone (which receives them from Complex I or II) and pumps 44 H++.

      • Complex 44 (Cytochrome c oxidase): Accepts electrons from Cytochrome c and pumps 22 H++ while simultaneously transferring electrons to O2.

      • Complex 22 (Succinate dehydrogenase): Accepts electrons directly from FADH2 (which is part of the Krebs cycle) but does not directly pump protons.

    • The re-entry of H++ ions into the mitochondrial matrix via ATP synthase is the direct driving force for ATP creation.

    • The general stoicheometric ratio for ATP generation is that approximately 44 H++ are required to flow through ATP synthase to produce 11 ATP.

  • ATP Yield from NADH++:

    • NADH++ brings electrons and H++ to Complex 1 of the ETC.

    • Electrons then travel through Complex 1 ightarrowightarrow Ubiquinone (Q) ightarrowightarrow Complex 3 ightarrowightarrow Cytochrome c ightarrowightarrow Complex 4.

    • This electron transport pathway, involving Complexes 1, 3, and 4, results in a total of 1010 H++ being pumped into the intermembrane space (44 from Complex 1, 44 from Complex 3, and 22 from Complex 4).

    • These 1010 H++ then re-enter the matrix via ATP synthase.

    • Net Gain: Approximately 2.52.5 ATP per NADH++ (1010 H++ pumped / 44 H++ per ATP = 2.52.5 ATP).

  • ATP Yield from FADH2:

    • FADH2 brings electrons and H++ to Complex 2, bypassing Complex 1.

    • Electrons then travel through Complex 2 ightarrowightarrow Ubiquinone (Q) ightarrowightarrow Complex 3 ightarrowightarrow Cytochrome c ightarrowightarrow Complex 4.

    • This pathway, involving Complexes 3 and 4 (Complex 2 does not pump H++), results in a total of 66 H++ being pumped into the intermembrane space (00 from Complex 2, 44 from Complex 3, and 22 from Complex 4).

    • These 66 H++ then enter the matrix via ATP synthase.

    • Net Gain: Approximately 1.51.5 ATP per FADH2 (66 H++ poured / 44 H++ per ATP = 1.51.5 ATP).

Aerobic: Oxidative Phosphorylation Products (Total ATP from Glucose/Glycogen)

  • This section summarizes the complete ATP yield from the aerobic metabolism of one glucose or glycogen molecule.

  • Phase 1 (Glycolysis to Pyruvate): Occurs in the cytoplasm.

    • Direct ATP: Net 22 ATP if starting from glucose (4 produced, 2 consumed), or 33 ATP if starting from glycogen (1 consumed).

    • NADH++: 22 NADH++ are produced. These must be transported into the mitochondrial matrix via shuttle systems (e.g., malate-aspartate shuttle or glycerol-phosphate shuttle) to enter the ETC.

    • Pyruvate: 22 Pyruvate molecules are formed from one glucose molecule.

  • Phase 1 (Pyruvate to Acetyl-CoA - Bridge Step): Occurs in the mitochondrial matrix.

    • NADH++: 22 NADH++ are produced (one from each of the 22 pyruvate molecules as they are converted to Acetyl-CoA). These then proceed to the ETC.

  • Phase 2 (Krebs Cycle - Citric Acid Cycle): Occurs in the mitochondrial matrix, with two turns per glucose molecule (one for each Acetyl-CoA).

    • Direct ATP: 22 ATP (or GTP, which is rapidly converted to ATP) are produced directly (one from each of the 22 Acetyl-CoA molecules).

    • NADH++: 66 NADH++ are produced (three from each of the 22 Acetyl-CoA molecules).

    • FADH2: 22 FADH2 are produced (one from each of the 22 Acetyl-CoA molecules).

  • Phase 3 (ETC) - ATP from Electron Carriers: Occurs on the inner mitochondrial membrane.

    • Total NADH++ brought to ETC:

      • 22 (from Glycolysis) + 22 (from Pyruvate oxidation) + 66 (from Krebs Cycle) = 1010 NADH++.

      • ATP from NADH++: 10×2.5=2510×2.5=25 ATP.

    • Total FADH2 brought to ETC:

      • 22 (from Krebs Cycle) = 22 FADH2.

      • ATP from FADH2: 2×1.5=32×1.5=3 ATP.

  • Total ATP Gain:

    • Summing all direct and indirect ATP produced from one glucose molecule:

      • 22 (direct ATP from glycolysis) + 22 (direct ATP from Krebs) + 2525 (from NADH++ in ETC) + 33 (from FADH2 in ETC) = 3232 ATP.

    • If starting with muscle glycogen, less ATP is expended in glycolysis, resulting in an additional direct ATP, making the total ATP 3333 ATP per molecule of glycogen.

    • Therefore, considering the variable direct ATP from glycolysis, the total yield is 3232 to 3333 ATP per molecule of glucose or glycogen fully catabolized under aerobic conditions.

Aerobic: Free Fatty Acid (FFA) Oxidation

  • Triglycerides (TG) are the primary storage form of fat in the body, found in adipose tissue and intramuscular triglyceride (IMTG) stores.

    • They serve as a major energy source, particularly during prolonged, low-to-moderate intensity exercise and at rest.

  • TG are broken down through a process called lipolysis into glycerol and 33 free fatty acids (FFAs).

    • This reaction is catalyzed by enzymes such as hormone-sensitive lipase (HSL) and lipoprotein lipase (LPL).

    • Glycerol can be transported to the liver and converted into a glycolytic intermediate.

    • FFAs are the main energy-yielding components that enter muscle cells.

  • The rate of FFA entry into muscle fibers from the bloodstream is highly dependent on the FFA concentration gradient between the blood and the muscle cell.

    • Higher blood [FFAs] (e.g., during fasting, prolonged exercise, or high-fat diets) generally leads to a higher rate of transportation into muscle fibers.

    • This transport is facilitated by specific proteins on the muscle cell membrane, such as fatty acid translocase (FAT/CD36) and fatty acid-binding proteins (FABPpm).

  • Fat oxidation yields significantly more ATP per molecule than glucose oxidation, approximately 33 to 44 times more ATP when considering equivalent mass of fuel.

    • This higher yield is due to the higher carbon-to-oxygen ratio in fatty acids, which allows for the production of more electron carriers (NADH+ and FADH2) during their breakdown.

  • However, fat oxidation is a much slower oxidation process compared to carbohydrate metabolism.

    • It requires more enzymatic steps and oxygen per unit of ATP produced, meaning it cannot provide energy as rapidly as carbohydrate or phosphocreatine systems.

    • This makes fat a less dominant fuel source during high-intensity, rapid energy-demanding activities.

Fat Oxidation – ββ-Oxidation (Phase 1)

  • ββ-oxidation is the primary metabolic pathway for fatty acid catabolism, occurring in the mitochondrial matrix (and peroxisomes for very long-chain FFAs).

    • It is a cyclical series of four enzymatic steps that systematically remove 22-Carbon Acyl units from the carboxyl end of a fatty acyl-CoA molecule.

  • Each complete cycle of ββ-oxidation produces:

    • 11 FADH2: Generated during the first oxidation step, which then delivers electrons directly to Complex II of the ETC.

    • 11 NADH++: Generated during the second oxidation step, which delivers electrons to Complex I of the ETC.

    • 11 Acetyl-CoA: This 22-carbon unit is cleaved off and then directly enters the Krebs cycle for further oxidation.

  • The ββ-oxidation process repeats until the entire fatty acid chain is converted into Acetyl-CoA molecules.

    • For example, a 1616-carbon saturated fatty acid (like palmitoyl-CoA) would undergo 77 cycles of ββ-oxidation, yielding 88 Acetyl-CoA molecules, 77 FADH2, and 77 NADH++.

  • The FADH2 and NADH++ produced during ββ-oxidation deliver their electrons to the ETC, generating a substantial amount of ATP.

  • The Acetyl-CoA molecules, in turn, enter the Krebs cycle to produce more electron carriers (NADH++ and FADH2) and a small amount of direct ATP, along with the release of CO2O2​.