A 2-year-old boy exhibits signs of muscle weakness, especially after prolonged exercise. A muscle biopsy shows lipid deposition and low carnitine level. What are the causes of these symptoms? For answer: a) Explain what hormone is released during prolon

Based on the symptoms and muscle biopsy findings you’ve described, the condition may be related to a primary carnitine deficiency or a defect in fatty acid metabolism, potentially pointing to a systemic issue with mitochondrial fatty acid oxidation. ### a) Hormone released during prolonged exercise: During prolonged exercise, the primary hormone released is **epinephrine** (adrenaline). **Signal Transduction of Epinephrine:** 1. **Epinephrine binds to adrenergic receptors (e.g., β2-adrenergic receptor) on the target cell (e.g., muscle or adipose tissue).** 2. **Receptor Activation:** This binding activates the Gs protein, which then activates adenylate cyclase. 3. **cAMP Production:** Adenylate cyclase converts ATP to cyclic AMP (cAMP). 4. **PKA Activation:** Increased levels of cAMP activate protein kinase A (PKA). 5. **Targets for PKA:** PKA phosphorylates various substrates leading to: - Activation of glycogen phosphorylase (increasing glycogen breakdown) - Inhibition of glycogen synthase (reducing glycogen synthesis) - Activation of lipolysis in adipose tissue. ### b) Scheme of fatty acids transport from cytosol to mitochondria: To transport long-chain fatty acids into the mitochondria, carnitine is key. 1. **Fatty Acyl-CoA is generated in the cytosol from fatty acids.** 2. **Fatty Acyl-CoA interacts with carnitine to form Fatty Acylcarnitine.** (Enzyme: Carnitine acyltransferase I) 3. **Fatty Acylcarnitine is transported across the mitochondrial membrane by a translocase.** 4. **Inside the mitochondria, Fatty Acylcarnitine is converted back to Fatty Acyl-CoA** (Enzyme: Carnitine acyltransferase II). ### c) Scheme of fatty acid oxidation: 1. **Activation:** Fatty acids are activated to Fatty Acyl-CoA in the cytosol. 2. **Transport:** Fatty Acyl-CoA is transported into the mitochondria as Fatty Acylcarnitine. 3. **Beta-Oxidation Cycle:** a. **1. Oxidation:** - Enzyme: Acyl-CoA dehydrogenase → forms trans-Δ²-enoyl-CoA + FADH₂. b. **2. Hydration:** - Enzyme: Enoyl-CoA hydratase → forms L-3-hydroxyacyl-CoA. c. **3. Oxidation:** - Enzyme: 3-hydroxyacyl-CoA dehydrogenase → forms 3-ketoacyl-CoA + NADH. d. **4. Thiolysis:** - Enzyme: Acyl-CoA acetyltransferase → releases Acetyl-CoA + Fatty Acyl-CoA shortened by two carbons. ### d) Reaction catalyzed by NAD+- dependent dehydrogenase: The general reaction for **3-hydroxyacyl-CoA dehydrogenase** is: \[ \text{3-hydroxyacyl-CoA} + NAD^+ \rightarrow \text{3-ketoacyl-CoA} + NADH + H^+ \] **Electron Transport Chain (ETC) from NADH to Oxygen:** NADH donates electrons to Complex I (NADH dehydrogenase) in the electron transport chain leading to: - Electrons travel through Complex I → Ubiquinone (CoQ) → Complex III (cytochrome bc1) → Cytochrome c → Complex IV (cytochrome c oxidase) → Oxygen (O2), which is reduced to H2O. ### e) Calculation of ATP production when one mole of oleic acid is oxidized to CO₂ and H₂O: **Steps for calculations:** 1. **Oleic acid (C18H34O2) is fully oxidized:** - **Number of cycles of β-oxidation:** \[(n/2) - 1 = (18/2) - 1 = 8\] cycles. - Each cycle generates: - 1 FADH2 (1.5 ATP) - 1 NADH (2.5 ATP) Total from 8 cycles: - FADH2: \(8 \times 1.5 = 12\) ATP - NADH: \(8 \times 2.5 = 20\) ATP 2. **Final Acetyl-CoA produced:** - \(C18 \text{ yields } 9 \text{ Acetyl-CoA}\) - \(1 Acetyl-CoA \text{ yields } 10 \text{ ATP (from TCA cycle)}\) - Total from Acetyl-CoA: \(9 \times 10 = 90\) ATP 3. **Total ATP yield:** - From β-oxidation + TCA cycle: \[ \text{Total ATP} = 12 + 20 + 90 = 122 \text{ ATP} \] 4. **2 ATP are consumed for activation of fatty acid to fatty acyl-CoA:** \[ \text{Net ATP} = 122 - 2 = 120 \text{ ATP} \] Thus, the complete oxidation of one mole of oleic acid yields approximately **120 ATP.** This detailed overview addresses all your points regarding muscle weakness due to carnitine deficiency and oxidation of fatty acids in the context of the symptoms described. Update (2024-09-30): The symptoms exhibited by the 2-year-old boy suggest a metabolic disorder, potentially relating to fatty acid oxidation due to the low levels of carnitine and the presence of lipid deposition in the muscle biopsy. Here are the components of the response as requested: ### a) Hormone Released During Prolonged Exercise The hormone primarily released during prolonged exercise is **glucagon**. #### Signal Transduction of Glucagon: 1. **Binding**: Glucagon binds to the glucagon receptor (a G protein-coupled receptor) on the target tissue (e.g., liver). 2. **G Protein Activation**: This activates the G protein (Gs), leading to the activation of adenylate cyclase. 3. **cAMP Production**: Adenylate cyclase converts ATP to cyclic AMP (cAMP). 4. **Protein Kinase Activation**: cAMP activates Protein Kinase A (PKA). 5. **Enzyme Activation/Inhibition**: PKA phosphorylates various enzymes: - Activates phosphorylase kinase (that converts glycogen to glucose). - Inhibits glycogen synthase, reducing glycogen synthesis. The primary processes activated in the liver include glycogenolysis (breakdown of glycogen to glucose) and gluconeogenesis (formation of glucose from non-carbohydrate sources). ### b) Fatty Acids Transport from Cytosol to Mitochondria Fatty acids are transported into the mitochondria in a two-step process involving carnitine: 1. **Activation**: Fatty acids in the cytosol are activated to acyl-CoA by the enzyme **Acyl-CoA synthetase**. \[ \text{Fatty Acid} + \text{ATP} + \text{CoA} \rightarrow \text{Fatty Acyl-CoA} + \text{AMP} + \text{PPi} \] 2. **Transport**: Acyl-CoA is converted to acyl-carnitine by **Carnitine acyltransferase I** (CAT I), allowing it to be transported across the mitochondrial membrane. Once inside, **Carnitine acyltransferase II** (CAT II) converts acyl-carnitine back to acyl-CoA in the mitochondrial matrix. ### c) Fatty Acids Oxidation The process of fatty acid oxidation occurs through a series of reactions known as β-oxidation in the mitochondria. The enzymes involved are: 1. **Acyl-CoA Dehydrogenase**: Converts acyl-CoA to trans-enoyl-CoA, producing FADH2. 2. **Enoyl-CoA Hydratase**: Converts trans-enoyl-CoA to L-3-hydroxyacyl-CoA. 3. **3-Hydroxyacyl-CoA Dehydrogenase**: Converts L-3-hydroxyacyl-CoA to 3-ketoacyl-CoA, producing NADH. 4. **Beta-Ketothiolase**: Cleaves 3-ketoacyl-CoA to Acyl-CoA and acetyl-CoA, which enters the citric acid cycle. ### d) NAD-Dependent Dehydrogenase Reaction The reaction catalyzed by NAD-dependent dehydrogenase (e.g., 3-Hydroxyacyl-CoA Dehydrogenase) is: \[ \text{L-3-Hydroxyacyl-CoA} + \text{NAD}^{+} \rightarrow \text{3-Ketoacyl-CoA} + \text{NADH} + \text{H}^{+} \] #### Electron Transport Chain (ETC) from NADH to Oxygen: 1. **NADH** donates electrons to Complex I (NADH dehydrogenase). 2. Electrons go to **Coenzyme Q (ubiquinone)**, reducing it to ubiquinol (QH2). 3. Electrons are transferred from QH2 to **Complex III (cytochrome bc1)**. 4. From Complex III, the electrons go to **cytochrome c**. 5. Finally, cytochrome c donates the electrons to **Complex IV (cytochrome c oxidase)**, which reduces molecular oxygen to water (O2 + 4e^- + 4H^+ → 2H2O). ### e) Calculate ATP Production from Oxidation of Oleic Acid Oleic acid (C18:1) undergoes β-oxidation a total of 9 times, yielding 9 molecules of acetyl-CoA: - Each acetyl-CoA entering the citric acid cycle generates: - 3 NADH → 3 × 2.5 = 7.5 ATP - 1 FADH2 → 1 × 1.5 = 1.5 ATP - 1 ATP (GTP) = 1 ATP - Total per acetyl-CoA = 7.5 + 1.5 + 1 = 10 ATP For 9 acetyl-CoA: \[ 9 \times 10 = 90 \text{ ATP} \] Additionally, 8 FADH2 are produced during β-oxidation: \[ 8 \times 1.5 = 12 \text{ ATP} \] And 8 NADH are produced during the process: \[ 8 \times 2.5 = 20 \text{ ATP} \] Total ATP production: \[ 90 + 12 + 20 = 122 \text{ ATP} \] ### Summary The child's symptoms may be related to a disorder in fatty acid metabolism, leading to exercise intolerance and lipid buildup in muscles. The provided components elucidate the hormonal signaling involved in energy mobilization during prolonged exercise, the transport and oxidation of fatty acids, and the energy yield from the complete oxidation of oleic acid.