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Metabolic Muscle Diseases - II


INTRODUCTION  — Patients with metabolic myopathies have underlying defects of energy production in muscle. Most affected patients have dynamic symptoms, such as exercise intolerance, muscle pain, and cramps upon exercise, rather than static symptoms, such as a fixed weakness of a specific muscle group.

To better understand these disorders, this topic review provides an overview of energy metabolism in muscle. The classification, diagnosis, and treatment of the metabolic myopathies are presented separately. (See

"Approach to the metabolic myopathies"

"Causes of metabolic myopathies" and

"Overview of disorders of glycogen metabolism" and

"Mitochondrial myopathies: Clinical features and diagnosis")

Prior to a review of the pathways of energy metabolism, it is helpful to first briefly review the sources of energy in muscle.

ENERGY SUBSTRATES IN EXERCISING MUSCLE. The main types of "fuel" used by muscle for energy metabolism are glycogen, glucose, and free fatty acids [ ]. The particular energy sources used by working muscle for aerobic metabolism depend upon a number of factors including the intensity, type, and duration of exercise, physical conditioning, and diet [,5 ]:
  1. At rest, muscle predominantly uses fatty acids [ ].

  2. During high-intensity, isometric exercise, anaerobic glycolysis, and the creatine kinase reaction, in which phosphocreatine is converted to adenosine triphosphate (ATP), are the primary sources of energy [ ].

  3. With submaximal exercise, the type of substrate used by muscle is heavily dependent upon the relative intensity of exercise. During low-intensity submaximal exercise, the main sources of energy are blood glucose and free fatty acids. With high-intensity submaximal exercise, the proportion of energy derived from glycogen and glucose is increased, and glycogen becomes the main source. Fatigue is experienced when glucose and glycogen stores are depleted (as when a marathon runner hits the "wall").

Sources of muscle energy also vary with the duration of exercise. During the first hour of mild, low-intensity exercise (such as jogging), glucose, glucagon, and free fatty acids are the major sources of energy. The uptake of free fatty acids by muscle increases substantially during one to four hours of mild to moderate prolonged exercise; after four hours, lipid oxidation becomes the major source of energy ( table 1) [ ]. (See "Exercise physiology".)

ENERGY METABOLISM IN MUSCLE  — Muscle contraction and relaxation depend primarily upon energy derived from hydrolysis of adenosine triphosphate (ATP). A number of biochemical processes in muscle fibers are responsible for maintaining a constant supply of ATP. These include:
  1. Glycogen or glucose metabolism

  2. Oxidative phosphorylation

  3. Creatine kinase (CK) reaction by which phosphocreatine is converted to ATP

  4. Purine nucleotide cycle

  5. Lipid metabolism

Glycogen or glucose metabolism — Energy generation via the metabolism of glycogen or glucose in muscle occurs either anaerobically or aerobically.

Anaerobic glycolysis — Anaerobic glycolysis supplies energy in relatively rare circumstances. This pathway is primarily used during conditions of high-intensity, sustained, isometric muscular activity (eg, lifting heavy objects), particularly in the setting of limited blood flow and oxygen supply to exercising muscle fibers.

Phosphorylase, phosphorylase b kinase, and the debranching enzymes are responsible for the production of glucose-1-phosphate from glycogen ( figure 1) [ ].

The rate-limiting step in glycolysis, however, is the conversion of fructose-6-phosphate to fructose-1,6-diphosphate by the enzyme phosphofructokinase (PFK). The last step in glycolysis is the conversion of pyruvate to lactate by lactate dehydrogenase.

The development of fatigue is related to the increased concentration of lactate within muscle fibers, thereby resulting in acidification of the muscle cell. The accumulation of inorganic phosphate (Pi), adenosine diphosphate (ADP), and the monovalent form of organic phosphate are also important in fatigue generation [,9 ].

As an example, maximal acute exercise to exhaustion is associated with a systemic pH as low as 6.80 and serum lactate concentrations as high as 20 to 25 meq/L [ ].

Aerobic glycolysis — During dynamic forms of exercise (isotonic), such as walking or running, aerobic glycolysis appears to play an important role in energy production. With aerobic glycolysis, pyruvate is formed through the same steps described in anaerobic glycolysis, but oxidative decarboxylation of pyruvate takes place through the pyruvate dehydrogenase complex, generating acetyl coenzyme A (acetyl-CoA). The latter compound enters the tricarboxylic acid (TCA) cycle, also known as the citric acid cycle or Krebs cycle, where it is converted into carbon dioxide and water ( figure 2) [,12 ].

Oxidative phosphorylation  — The oxidative phosphorylation system, localized in the inner mitochondrial membrane, is the main source of energy in muscle and other cells ( figure 2). Compared to glycolysis, this system produces 17 to 18 times as much adenosine triphosphate (ATP) from the same amount of glucose.

The respiratory chain is composed of four multi-subunit complexes (I, II, III, and IV) linked by the mobile electron carriers coenzyme Q and cytochrome c. The reduced forms of nicotinamide adenine dinucleotide (NADH) and flavin adenine dinucleotide (FADH2) are formed from the citric acid cycle and the beta-oxidation of fatty acids in the mitochondrial matrix. The respiratory chain transfers electrons from NADH (via complex I) and from reduced flavoproteins (via complex II and electron transfer flavoprotein-coenzyme Q oxidoreductase [ETF- Qo]) to coenzyme Q, then complex III, cytochrome c and finally complex IV, where they combine with molecular oxygen to form water. The flow of electrons releases energy that is used in the phosphorylation of ADP to ATP by complex V (ATP synthetase), which is also embedded in the inner mitochondrial membrane [,14 ].

Phosphocreatine pathway  — During very high intensity exercise, rapid formation of ATP can be accomplished through the reaction of phosphocreatine with ADP catalyzed by creatine kinase. Because the amount of phosphocreatine in muscle is small, the duration of this reaction is very brief. When oxygenation of muscle again becomes adequate, stores of phosphocreatine are replenished.

Purine nucleotide cycle  — Intensely exercising muscle can generate ATP over a short period of time using the adenylate kinase reaction; this reaction catalyzes the conversion of two ADP molecules into one molecule of ATP and one molecule of adenosine monophosphate (AMP). The AMP may then be deaminated to inosine monophosphate (IMP) by myoadenylate deaminase, with concurrent production of ammonia (href=" figure 3) [ ]. Myoadenylate deaminase activity seems to be higher in type 2, fast muscle fibers.

Lipid metabolism  — The metabolism of lipids in muscle occurs via beta- and omega-oxidation of fatty acids.

Beta-oxidation of fatty acids  — At rest, fatty acids are the major energy substrate for muscle. Long-chain fatty acids constitute a major source of energy for prolonged, low-intensity exercise, lasting for more than 40 to 50 minutes [ ]. Fatty acids are derived from circulating, very low-density lipoproteins in the bloodstream or from triglycerides stored in adipocytes.

Once in the cytoplasm, short- and medium-chain fatty acids of less than 10 carbon atoms can cross both the outer and inner mitochondrial membranes; these compounds subsequently enter the mitochondrial matrix where they undergo beta-oxidation after activation into their CoA esters ( figure 4).

However, the mitochondrial membrane is not permeable to long-chain fatty acids; a multi-step process is therefore required for these compounds to be used by mitochondria. In the muscle cytoplasm, long-chain fatty acids are first activated by long-chain acyl-CoA synthetase to their CoA thioesters. The CoA thioesters are subsequently linked with carnitine  by the enzyme carnitine palmitoyltransferase I (CPT I), which is located on the inner side of the outer mitochondrial membrane. The acylcarnitine form of the long-chain fatty acid, palmitoylcarnitine, is then transferred across the inner mitochondrial membrane by carnitine:acylcarnitine translocase [ ]; once in the mitochondrial matrix, it is converted back to free acyl-CoA derivative and carnitine by CPT II, which is localized on the inner side of the inner mitochondrial membrane ( figure 4).

Once carnitine  is released, the long-chain acyl-CoA derivative enters the beta-oxidation pathway. With every complete cycle, a two-carbon fragment is cleaved and an acetyl-CoA molecule is released. The acetyl-CoA is then oxidized via the citric acid cycle for energy production in muscle, heart, and other tissues ( figure 2) [ ].

Ninety percent of the hepatic acetyl-CoA, however, is converted into ketones, which are an important source of energy for all tissues, particularly the brain. During prolonged fasting, ketones provide an important source of energy in brain tissue because the blood-brain barrier is impermeable to long-chain fatty acids [ ]. The intramitochondrial beta-oxidation of fatty acids requires the existence of chain-length specific enzymes. The complete oxidation of fatty acids is mediated by at least 11 enzymes ( table 1) [,20 ].

Omega-oxidation of fatty acids  — During prolonged fasting, as much as 20 percent of total cellular oxidation of fatty acids is accomplished in liver peroxisomes through omega-oxidation, thereby resulting in the formation of dicarboxylic acids (DCAs). DCAs are further metabolized through mitochondrial beta-oxidation.

The peroxisomal fatty acid oxidation enzymes are genetically distinct from the mitochondrial enzymes [ ]. In mitochondria, the first step of beta-oxidation occurs via a flavin adenine dinucleotide (FAD)-containing enzyme coupled to oxidative phosphorylation that generates adenosine triphosphate (ATP). In peroxisomes, however, beta-oxidation occurs via a flavin-containing oxidase that generates H2O2 and then, through peroxisomal catalase, H2O and O2 [ ]. Therefore, some energy is wasted. In mitochondria, the next steps in beta-oxidation are managed by two separate enzymes, while in peroxisomes they are managed by a single multifunctional enzyme protein.

It is believed that fatty acid oxidation in peroxisomes handles very-long-chain fatty acids (>C22), because these accumulate, particularly in neural tissues, in genetically linked peroxisomal disorders such as Zellweger syndrome and adrenoleukodystrophy. (See "Peroxisomal disorders".)

In metabolic defects of intramitochondrial fatty acid oxidation, mitochondrial beta-oxidation of DCAs is impaired at a time when the production of DCAs is increased due to the recruitment of peroxisomal omega-oxidation [ ], hence the detection of DCAs in the urine. However, DCAs are also produced in other settings, including normal fasting, diabetic ketoacidosis, and diets containing medium-chain triglycerides. In addition, thioesterases catalyze the deacylation of coenzyme A and the conjugation of the acyl groups to glycine and to carnitine  [,24 ]. Thus, the detection of acylcarnitine derivatives in serum, and the detection of dicarboxylic acids and acylglycines in urine, has proven useful in the diagnosis of inborn errors of fatty acid oxidation [,26 ].

Impairments at any of the important regulatory steps of lipid metabolism can lead to a myopathy and, in some cases, involvement of other organs. (See "Causes of metabolic myopathies".)

Интересный момент - дисфункция митохондрий может вызвать проблему выработки желудочной кислоты (очень энергозатратный процесс) И работу костного мозга и как следствие дифицит гемоглобина и от туда уже другие проблемы. Так же дисфункция митохондрий может вызывать проблемы с щитовидкой и регулированием сахара. Хотя говорят, что анемия и дефицит желаза маловероятны как причина сбоя в митохондриях, хоть железо и является необходимым элементов для ферментов в митохондрии. Про медь не понятно. Но куча других факторов может влиять на митохондрию. Всё закольцовано и работает как в одну сторону, так и в другую.

Tags: Диагностика, Причины, Фармакология

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