Lipotoxicity may result when flux of NEFAs into the circulation and uptake by a

Question

Lipotoxicity may result when flux of NEFAs into the circulation and uptake by a skeletal myocyte exceed the ability of its oxidation or storage pathways to dispose of fatty acyl CoAs. LIST the respective final products of skeletal muscle oxidation and storage pathways. LIST two intermediates that may accumulate when [Fatty Acyl CoAs] exceed the capacity of skeletal muscle oxidation and storage pathways and EXPLAIN IN DETAIL the MECHANISMS by which these intermediates may affect insulin signaling, insulin sensitivity, and glucose transport in skeletal muscle. Include the following terms in your response: Serine, Tyrosine, IRS, PKB, PKC, GLUT4, kinase, theta, and phosphorylation

Explanation / Answer

Skeletal muscle is unique in energy metabolism. In addition to its aerobic capacity, it is adapted for short-term anaerobic activity, allowing for both extended lower intensity endurance physical activity and short-term high-energy output. Muscle metabolism can be understood from a set of basic statements about the biochemical energy balance:

• Chemical energy is stored in muscle cells as ATP and creatine phosphate, which are biochemical capacitors;

• ATP provides the energy for all forms of muscle work;

• ATPases, the enzymes that break down ATP and release the energy for muscle work and metabolism, are the demand side of the balance and define energetic states; and • This demand is supplied mainly by continuous aerobic metabolism.

Energy in skeletal muscle is derived mostly from glucose and fatty acids. It is also stored in significant amounts as glycogen and triglycerides, respectively, in the muscle fibers. The chemical energy trapped within the bonds of the carbohydrate, lipid, and protein molecules is extracted as adenosine triphosphate (ATP), an immediate source of energy. Adenosine phosphates have energy receiver and donor cycles: ATP stores are replenished during the oxidation of energy sources and used during skeletal muscle work. ATP consists of an adenosine molecule linked to three phosphates. The bonds that link the molecule to the outermost phosphates are called high-energy phosphate bonds, since their hydrolysis (when ATP joins with water) releases 7.3 kcal of energy. This reaction is catalyzed by an enzyme called adenosine triphosphatase (ATPase), and the end product is an adenosine molecule containing two phosphate groups called adenosine diphosphate (ADP). Additional energy is produced when the second phosphate bond is hydrolyzed and a single phosphate containing adenosine monophosphate (AMP) is the end product.

Anerobic energy metabolism

Glycolysis is the pathway for the catabolism of glucose, occurring in the cytosol. Glycolysis is unique in that it can use oxygen if available (pyruvate acetyl-CoA), or function without oxygen (pyruvate lactate). The relative role of glycolysis as a source of energy varies between tissues (for example, slight in the heart, and major in the brain and red cells). In skeletal muscle, glycolysis permits high performance, when aerobic metabolism alone is not sufficient. In skeletal muscle at rest, glycolysis provides nearly half of the acetyl-CoA used in the citric acid cycle. In the process, 6 carbon glucose is catabolized to 3 carbon pyruvate and then to acetyl-CoA, resulting in a net production of 2 NADH and 2 ATP. NADH formed through glycolysis is transported via the malate shuttle into the mitochondria and oxidized in the respiratory chain, with a net yield of 2 ATP per NADH. Thus, in the complete oxidation of 1 mole of glucose under aerobic conditions, glycolysis yields 8 ATP and the citric acid cycle 30 ATP.

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