Metabolism of Muscle Cell

CARBOHYDRATE METABOLISM

Blood glucose enters the muscle fiber through a specialized muscle-specific glucose transporter. It is then phosphorylated to glucose-6-phosphate and undergoes glycolysis. Glucose-6-phosphate is also derived from degradative phosphorylation of muscle glycogen stores. Phosphorylase b kinase activates myophosphorylase that initiates glycogen breakdown, and a debranching enzyme completes the process by which glucose-1-phosphate is produced. This is also converted to glucose-6-phosphate and enters glycolysis.

The rate-limiting step in glycolysis is the conversion of fructose-1-phosphate to fructose-1,6-diphosphate by phosphofructokinase. Ultimately, one molecule of glucose is broken down into two molecules of pyruvate, and three molecules of ATP are generated. Under anaerobic conditions, pyruvate is converted to lactate. Under aerobic conditions, pyruvate is instead converted to acetyl-coenzyme A (acetyl-CoA) and enters the tricarboxylic acid (TCA), or Krebs, cycle. Within the mitochondria, this cycle generates carbon dioxide and water, as well as the reduced forms of nicotinamide and flavin adenine dinucleotide (NADH and FADH₂, respectively) and guanosine triphosphate (GTP) (which can transfer phosphate to ADP to produce ATP). NADH and FADH₂ then undergo oxidative phosphorylation in the inner mitochondrial membrane, generating additional ATP molecules. Therefore aerobic glycogen and glucose metabolism produces much more ATP than anaerobic glycolysis.

LIPID METABOLISM

Nonesterified fatty acids (NEFAs) enter the muscle fiber from the bloodstream, derived from circulating very-low-density lipoproteins and triglycerides stored in adipocytes. Free fatty acids are first activated to their acyl-coenzyme A (acyl-CoA) thioesters. Short- and medium-chain fatty acyl-CoAs can cross the mitochondrial membranes, where they undergo beta oxidation. Long-chain fatty acyl-CoAs cannot undergo beta oxidation and require esterification with carnitine by carnitine palmitoyltransferase I (CPT I). The resultant palmitoylcarnitine is then transferred across the inner mitochondrial membrane and converted back into the long-chain fatty acyl-CoA by CPT II. The long-chain fatty acyl-CoA derivative then can enter the beta-oxidation pathway. Beta oxidation occurs via fatty acid chain length–specific enzymes, producing acetyl-CoA that can then enter the Krebs cycle.

Energy utilization in muscle is activity dependent; that is, the specific energy source is dependent upon the level and intensity of activity, type of activity, duration of activity, conditioning, and diet. At rest, the predominant energy source is fatty acids, particularly long-chain fatty acids. During low level, low-intensity exercise, the muscle primarily utilizes glucose and fatty acids. With increasing intensity, glucose utilization is increased, and muscle glycogen becomes a principle energy source. With maximal, isometric exercise, anaerobic glycolysis is the primary source. Also, during long-duration low-level exercise, lipid metabolism becomes the main source of energy.

A classic example of a defect of carbohydrate metabolism is McArdle syndrome, or myophosphorylase deficiency. Here the deficiency in activity of myophosphorylase leads to the inability to initiate glycogen breakdown. This leads to accumulation of glycogen in the muscle. Because there is no ability to utilize glycogen as an energy source, there is a reduction in the production of pyruvate. As a result, less acetyl-CoA is available to go through the Krebs cycle, and less NADH and FADH₂ undergo oxidative phosphorylation. Patients develop exercise intolerance with myalgia, fatigability, and exertional weakness, and potentially rhabdomyolysis. This is more common with isometric or sustained moderate-intensity exercise. Patients typically experience a “second wind,” whereby a brief rest or reduction in activity leads to improved exercise tolerance. This correlates to increased availability of blood glucose and free fatty acids.

The most common disorder of lipid metabolism is CPT II deficiency. CPT II deficiency causes an inability to convert long-chain palmitoylcarnitines back into long-chain fatty acyl-CoAs on the inner mitochondrial membrane. Therefore the long-chain fatty acyl-CoAs cannot enter the beta-oxidation pathway, and cannot produce acetyl-CoA to enter the Krebs cycle. Patients develop exercise intolerance and exertional rhabdomyolysis after prolonged exercise, rather than brief, intense exercise, and experience no “second-wind” phenomenon.

Only gold members can continue reading. Log In or Register to continue