Muscle oxidative phosphorylation

Clofibrate causes a necrotizing myopathy, particularly in patients with renal failure, nephrotic syndrome or hypothyroidism. The myopathy is painful and myokymia of unknown origin is sometimes present. The mechanism of damage is not known, but p-chlorophenol is a major metabolite of clofibrate and p-chlorophe-nol is a particularly potent uncoupler of cellular oxidative phosphorylation and disrupts the fluidity of lipid membranes. Muscle damage is repaired rapidly on the cessation of treatment. 

Corticosteroids a chronic painless myopathy associated with the long-term use of corticosteroids is a particularly common example of drug-induced muscle disorder. It is almost certain that mild cases are overlooked because steroids are so frequently used to treat inflammatory myopathies such as polymyositis. Fluorinated steroids are particularly frequently implicated, and the incidence of drug-induced muscle disease is dose and time-related. The presence of muscle weakness can even complicate topical steroid therapy. Corticosteroid-induced myopathy is mediated via intramuscular cytosolic steroid receptors. The steroid-receptor complexes inhibit protein synthesis and interfere with oxidative phosphorylation. The myopathy is associated with vacuolar changes in muscle, and the accumulation of cytoplasmic glycogen and mitochondrial aggregations. 

Figure 12-14. The creatine phosphate shuttle of heart and skeletal muscle. The shuttle allows rapid transport of high-energy phosphate from the mitochondrial matrix into the cytosol. CKg, creatine kinase concerned with large requirements for ATP, eg, muscular contraction CIC, creatine kinase for maintaining equilibrium between creatine and creatine phosphate and ATP/ADP CKg, creatine kinase coupling glycolysis to creatine phosphate synthesis CK, , mitochondrial creatine kinase mediating creatine phosphate production from ATP formed in oxidative phosphorylation P, pore protein in outer mitochondrial membrane.

The ATP required as the constant energy source for the contraction-relaxation cycle of muscle can be generated (1) by glycolysis, using blood glucose or muscle glycogen, (2) by oxidative phosphorylation, (3) from creatine... 

Under Aerobic Conditions, Muscle Generates ATP Mainly by Oxidative Phosphorylation... 

Explain how creatine phosphate, oxidative phosphorylation, and glycolysis provide energy for skeletal muscle contraction... 

During the recovery period from exercise, ATP (newly produced by way of oxidative phosphorylation) is needed to replace the creatine phosphate reserves — a process that may be completed within a few minutes. Next, the lactic acid produced during glycolysis must be metabolized. In the muscle, lactic acid is converted into pyruvic acid, some of which is then used as a substrate in the oxidative phosphorylation pathway to produce ATP. The remainder of the pyruvic acid is converted into glucose in the liver that is then stored in the form of glycogen in the liver and skeletal muscles. These later metabolic processes require several hours for completion. 

Muscle contraction produces ADP if this cannot be recycled to ATP contraction will cease. Rephosphorylation of ADP by mitochondrial oxidative phosphorylation is an... 

Mitochondrial diseases are often expressed as neuropathies and myopathies because brain and muscle are highly dependent on oxidative phosphorylation. Mitochondrial genes code for some of the components of the electron transport chain and oxidative phosphorylation, as well as some mitochondrial tRNA molecules. 

The circular mitochondrial chromosome encodes 13 of the more than 80 proteins that comprise the major complexes of oxidative phosphorylation as well as 22 tRNAs and 2 rRNAs. Mutations in these genes affect highly aerobic tissues (nerves, muscle), and the diseases exhibit characteristic mitochondrial pedigrees (maternal inheritance). 

Figure 2.8 The ATP/ADP cycle. The major ATP-generating process from fuel oxidation is oxidative phosphorylation driven by electron transport in the mitochondria. In muscle, the major energy-requiring process is physical activity. The phosphate ion is omitted from the figure for the sake of simplicity.

In any cell that depends on aerobic metabolism, if the rate of ATP utilisation increases, the rate of the Krebs cycle, electron transfer and oxidative phosphorylation must also increase. The mechanism of regulation discussed here is for mammalian skeletal muscle since, to provide sufficient ATP to maintain the maximal power output, at least a 50-fold increase in flux through the cycle is required so that the mechanism is easier to study (Figure 9.22). 

Figure 9.25 Control of the Krebs q/cle and myosin-ATPase by direct effects of Ccf ions and the resultant effects on electron transfer and oxidative phosphorylation in muscle. The stimulation of the Krebs cycle by ions results in an increase in the NADH/NAD concentration ratio, which stimulates electron transfer. The stimulation of myosin-ATPase by Ca lowers the ATP/ADP concentration ratio, which also stimulates electron transfer. The Ca ions are released from the sarcoplasmic reticulum in muscle in response to nervous stimulation. In addition, generation of ADP by myosin ATPase increases the ADP concentration, which stimulates the cycle. Note that a lack of oxygen will prevent generation of ATP (Chapter 13).

Uncoupling of oxidative phosphorylation from respiration in brown adipose tissue and possibly other tissues (e.g. in muscle) (Chapter 9). 

Figure 19.18 The role of cyclic GMP and vasodilation in provision and preparation of spermatozoa for fertilisation. Vasodilation is regulated by the concentration of cyclic GMP by relaxation of smooth muscle. The resultant increase in blood flow to the corpora cavernosa results in erection of the penis for the ejaculation of spermatozoa into the vagina. The increase in blood flow to the vaginal smooth muscle provides more oxygen for diffusion into the lumen. Here it provides for oxidative phosphorylation in the mitochondria of the-mid section of the spermatozoa, which provides the ATP for the beating of the flagellum and hence for swimming to the oviduct for fertilisation.

Figure 22.17 Summary of mechanisms to maintain the ATP/ADP concentration ratio in hypoxic myocardium. A decrease in the ATP/ADP concentration ratio increases the concentrations of AMP and phosphate, which stimulate conversion of glycogen/ glucose to lactic acid and hence ATP generation from glycolysis. The changes also increase the activity of AMP deaminase, which increases the formation and hence the concentration of adenosine. The latter has two major effects, (i) It relaxes smooth muscle in the arterioles, which results in vasodilation that provides more oxygen for aerobic ATP generation (oxidative phosphorylation). (ii) It results in decreased work by the heart (i.e. decrease in contractile activity), (mechanisms given in the text) which decreases ATP utilisation.

Zebrafish larvae possess two types of skeletal muscle fibers. Slow (red) muscle fibers, a superficial monolayer on the siuface of the myotome, are equipped for oxidative phosphorylation, can generate relatively large stores of energy, and are most resistant to fatigue. Fast (white) muscle fibers, in the deep portion of the myotome, are least resistant to fatigue because they rely on anaerobic glycolysis for... 

In the preceding sections the conversion of purines and purine nucleosides to purine nucleoside monophosphates has been discussed. The monophosphates of adenosine and guanosine must be converted to their di- and triphosphates for polymerization to RNA, for reduction to 2 -deoxyribonucleoside diphosphates, and for the many other reactions in which they take part. Adenosine triphosphate is produced by oxidative phosphorylation and by transfer of phosphate from 1,3-diphosphoglycerate and phosphopyruvate to adenosine diphosphate. A series of transphosphorylations distributes phosphate from adenosine triphosphate to all of the other nucleotides. Two classes of enzymes, termed nucleoside mono-phosphokinases and nucleoside diphosphokinases, catalyse the formation of the nucleoside di- and triphosphates by the transfer of the terminal phosphoryl group from adenosine triphosphate. Muscle adenylate kinase (myokinase)... 

Using the transport systems in the membranes, cells regulate their volume, internal pH value, and ionic environment. They concentrate metabolites that are important for energy metabolism and biosynthesis, and exclude toxic substances. Transport systems also serve to establish ion gradients, which are required for oxidative phosphorylation and stimulation of muscle and nerve cells, for example (see p. 350). 

The pathology is due to decreased mitochondrial function, eg, impaired oxidative phosphorylation, and thus manifests in energy-intensive tissues, such as muscles and nerves. 

A. H. From and K. Ugurbil, Standard magnetic resonance based measurements of the Pi-ATP rate do not index the rate of oxidative phosphorylation in cardiac and skeletal muscles. Am. J. Physiol. Cell Physiol, 2011, 301, Cl-Cll. 

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