Muscle fibers develop tension and shorten, thereby producing movement. These processes, including contraction and relaxation, are coordinated by the nervous system and are energy-requiring. Skeletal muscle meets its energy demands by converting chemical energy into mechanical energy. One feature unique to skeletal muscle, compared with other tissues, is the energy requirement difference between its resting and fully active states, a value that can approach two to three orders of magnitude.';:! When the metabolic energy demands of active muscle cannot be met by the available energy sources, muscle fatigue and dysfunction occur. In such settings, when abnormalities of muscle biochemistry are responsible for the decreased energy supply, the term metabolic myopathies is applied. For diagnostic purposes, these disorders can be divided into two groups: (1) exercise-induced (dynamic) myopathies, in which symptoms such as weakness, cramping, myalgias, and stiffness appear during exercise; and (2) stable, or slowly progressive (static), myopathies (see Iable.S.2.5.-.2, and 25-3 ).'2] Muscle energy metabolism may be assessed through exercise testing. The results of these studies may
_TABLE 25-3 -- METABOLIC DEFECTS THAT PRODUCE STATIC MUSCLE WEAKNESS_
Disorders of carbohydrate metabolism
Acid maltase deficiency (type II glycogenosis)
Debrancher enzyme deficiency (type 111 glycogenosis)
Brancher enzyme deficiency (type IV glycogenosis)
Phosphorylase b kinase deficiency
Disorders of lipid metabolism
Muscle carnitine deficiency
Systemic carnitine deficiency
Modified from Rifai Z, Griggs RC. Metabolic myopathies. In Samuels MA, Feske S, Mesulam MM, et al (eds): Office Practice of Neurology. New York, Churchill Livingstone, 1996, pp 600-604.
refine the differential diagnosis and reduce the cost of the microscopic analysis. Additionally, when the microscopic evaluation is unrevealing, provocative exercise testing may confirm the presence of a metabolic defect. Common types of exercise testing include (1) forearm (grip) exercise that primarily provides information about the integrity of glycolytic metabolism; (2) incremental bicycle ergometry that yields information about the integrity of aerobic metabolism; and (3) 31 P magnetic resonance spectroscopy that provides information about the intracellular metabolites of energy metabolism (i.e., adenosine triphosphate [ATP], inorganic phosphate, and phosphocreatine). Because exercise testing is an important part of the investigation of muscle disease, particularly with disorders of skeletal muscle energy metabolism, it is essential that physicians understand skeletal muscle energy metabolism.
Although muscle contraction is ATP-consuming, the ATP content of a contracting muscle changes little during a sustained contraction. Interestingly, muscle ATP stores are incapable of sustaining a muscle contraction for more than a single second. Phosphocreatine, a high-energy compound with an intramuscular concentration approximately four- to five-fold that of ATP, permits rapid ATP regeneration through the rephosphorylation of adenosine diphosphate (ADP). This reaction is catalyzed by creatine kinase, an enzyme found in large quantities in skeletal muscle tissue. Nevertheless, this anaerobic energy source is depleted in less than a minute, and even when combined, these two sources of readily available energy are incapable of maintaining high-intensity exercise. For this reason, skeletal muscle tissue must rely on other energy sources when sustained exertion is necessary.
In the nonfasting individual, the energy requirements of skeletal muscle are met by the metabolism of either carbohydrate (e.g., glycogen, glucose) or lipid (e.g., free fatty acids). The principal source of carbohydrate for skeletal muscle metabolism is intracellular glycogen, which is ' formed from blood glucose, via glycogenesis, and stored within the myocyte. When energy is required, glycogen is hydrolyzed to glucose (glycogenolysis) and then to pyruvate (glycolysis). In addition to pyruvate, glycolysis also generates ATP and nicotinamide adenine dinucleotide hydrogen (NADH) (reduced form of nicotinamide adenine dinucleotide [NAD + ]). Under aerobic conditions, pyruvate is subsequently metabolized to acetyl-CoA. The latter compound enters the Krebs' (tricarboxylic acid) cycle, yielding further molecules of ATP and NADH, as well as flavin adenine dinucleotide hydrogen (FADH 2 ). The reducing equivalents generated by glycolysis and the Krebs' cycle (i.e., the NADH and FADH 2 ) enter the electron transport system, a chain of enzymes located on the inner mitochondrial membrane, and are oxidized. The energy released from their oxidation is used to drive the phosphorylation of ADP to ATP. The maximum derivable energy from the aerobic metabolism of one molecule of glucose is 38 molecules of ATP. Conversely, under anaerobic conditions, because pyruvate is converted to lactate and the generated reducing equivalents cannot be metabolized by the electron transport system, only four molecules of ATP are generated from one molecule of glucose. Hence, the metabolism of carbohydrate is much more energy-efficient in the presence of oxygen (i.e., aerobic metabolism) than in its absence (i.e., anaerobic metabolism). The skeletal muscle fatigue (i.e., the inability to maintain high-intensity exertion for more than several minutes) associated with anaerobic glycolysis results from end-product accumulation (ADP, inorganic phosphorus, hydrogen ion), not from a lack of oxygen. [i] Although blood glucose can be used directly, most carbohydrate energy is derived from glycogen. Unlike carbohydrate storage, which is primarily intramuscular, lipid storage is primarily extramuscular. For this reason, the primary source of lipids during skeletal muscle metabolism is plasma free fatty acids; the lipid present within the myocyte contributes to a much lesser extent. Since the rate of free fatty acid mobilization is slow, the contribution of lipid metabolism during initial energy generation is limited. In addition, although carbohydrate can undergo both aerobic and anaerobic metabolism, lipid can only be metabolized aerobically and consequently cannot be utilized during anaerobic conditions.
As expected, the exact ratio of carbohydrate and lipid utilized for muscle energy metabolism, a topic recently summarized in an editorial by Layzer,  reflects many variables, including the intensity of exertion and its duration, the blood concentration of free fatty acids and oxygen, the amount of blood flow to the muscle, the muscle glycogen concentration, and the muscle's capacity for oxidative metabolism. At rest and during light exercise, skeletal muscle tissue metabolism is aerobic, and consequently it aerobically metabolizes free fatty acids for its energy. As the degree of intensity increases, the supply of lipid-derived energy becomes unable to keep pace with the energy requirement. For this reason, a greater proportion of energy must be contributed by carbohydrate. In general, enough glycogen is available to work intensively for 3 to 4 hours.  Should effort continue after the glycogen supply is depleted, the slower rate of lipid metabolism immediately diminishes the magnitude of the ongoing effort. At maximum intensity (e.g., sprinting at full speed), skeletal muscle energy is supplied through anaerobic glycolysis. Initially, the readily available energy substrates are exhausted (i.e., aTp and phosphocreatine), and aerobic glycolysis begins. Although simultaneous changes enhance oxidative metabolism (i.e., increased blood flow to muscle, increased oxygen uptake), they are insufficient to meet the energy demands of maximum exertion. Thus, anaerobic glycolysis occurs and pyruvate is converted to lactate. As lactate accumulates, oxygen debt increases, a term that refers to the additional oxygen required, during recovery, to oxidize the accumulated lactate. Again, this level of exertion can be maintained only for several minutes.  Through aerobic exercise training, athletes enhance their muscles' capacity for oxidative (aerobic) metabolism. Thus, during submaximal efforts, the blend of substrate used contains a greater percentage of lipid and, for this reason, less glycogen. As a result, the glycogen supply lasts longer, as does the individual's endurance.
Forearm exercise testing can be performed in a number of ways. Traditionally, the patient was asked to repetitively
squeeze a handheld ergometer while a blood pressure cuff was maintained above systolic pressure. The blood pressure cuff, by inducing ischemia, ensures that oxidative phosphorylation cannot occur. A simple technique for evaluating lactate production in response to ischemic forearm exercise was described by Munsat in 1970.[6i In that report, rested and fasting individuals squeezed a handheld ergometer, with a workload of 4 to 7 kg-m, at 60 Hz for 1 minute. (Alternative methods are to sustain 1.5-second contractions that are separated by 0.5-second rest periods for 1 full minute M or squeezing a hand dynamometer to 50 percent of maximum grip strength until exhaustion--usually about 10 minutes. y ) Although the serum lactate concentrations vary significantly among the studied individuals (the standard deviation approximated 60 percent of the mean), their relative change (rather than their absolute change) is fairly constant for a given individual. The serum lactate concentration peaks within 5 minutes (within 3 minutes for 90 percent of the tested individuals) of work cessation at a value that is three- to five-fold greater than the initial resting value. Because ischemic work induces pain, it is fortunate that the best correlation between the degree of serum lactate rise and the total work performed occurs when the exercise period is limited to 1 minute, a period of ischemic exercise that most individuals can tolerate. The relationship of forearm work and lactate production without ischemia was also evaluated and appears to produce comparable results, provided the workload exceeds 6 to 7 kg-m. In other words, the work intensity must be sufficiently strenuous to exceed the individual's aerobic threshold, thereby inducing anaerobic energy metabolism. This technique avoids the use of blood pressure cuff-induced ischemia, which may be hazardous to patients with glycolytic defects (may cause severe muscle necrosis). y , y
Regardless of the technique used, the anaerobic condition blocks oxidative phosphorylation, thereby ensuring dependence on anaerobic glycolysis. Pre-exercise and postexercise (1, 2, 4, 6, and 10 minutes) venous lactate and ammonia levels are determined from venous blood samples collected from a catheter placed in an antecubital vein proximal to the deep veins of the forearm (e.g., the median vein). A three-way stopcock can be connected--blood samples are obtained from the side port and a slow infusion of normal saline maintains catheter patency. Normally, the lactate value rises three- to five-fold (resting level is mmo1/L) within 1 to 2 minutes, whereas the ammonia value rises two- to ten-fold within 2 to 5 minutes of exercise. y , y , [5 In the presence of a metabolic disorder, however, different metabolite patterns may be observed--with a defect in glycolysis, ammonia elevation occurs, but lactate elevation is diminished or does not occur. With myoadenylate deaminase deficiency, lactate elevation occurs, but elevation of ammonia does not. In the setting of mitochondrial disorders lactate elevation is excessive, and with poor effort, neither lactate nor ammonia concentrations increase. As expected, with disorders of lipid metabolism, the metabolite profile is normal. Although the major source of blood lactate is muscle, the blood lactate concentration rises with anxiety, hyperventilation, muscular activity, and food intake and, therefore, the patient should be relaxed, still, and in a fasting state. y
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