Muscles fatty acid oxidation

VyV thesize malonyl-CoA for fatty acid synthesis. Muscle cells do not synthesize fatty acids however, they do carefully regulate the oxidation of fatty acids through the synthesis and destruction of malonyl-CoA. ACC-1 is a cytosolic protein, whereas ACC-2 is mitochondrial, closely linked to CPT-I in the outer mitochondrial membrane. Mice that have been bred to lack ACC-2 have a 50% reduction of fat stores as compared with "normal" mice. This was shown to be attributable to a 30% increase in skeletal muscle fatty acid oxidation because of the dysregulation of CPT-I, because malonyl CoA could not be produced to regulate the rate at which fatty acid oxidation occurred. 

Additional information <2, 6> (<6> enzyme functions as a metabolic sensor that monitors cellular AMP and ATP levels [31] <2> phosphory-lates key target proteins that control flux through metabolic pathways of hepatic ketogenesis, cholesterol synthesis, adipocyte lipolysis and skeletal muscle fatty acid oxidation [30] <4> regulates triacylglycerolsynthesis and fatty acid oxidation in liver and muscle reciprocally [29]) [29-31]... 

Antidiabetic Drugs other than Insulin. Figure 3 The antihyperglycaemic effect of metformin involves enhanced insulin-mediated suppression of hepatic glucose production and muscle glucose uptake. Metformin also exerts non-insulin-dependent effects on these tissues, including reduced fatty acid oxidation and increased anaerobic glucose metabolism by the intestine. FA, fatty acid f, increase i decrease. 

Figure 3. Mitochondrial fatty acid oxidation. Long-chain fatty acids are converted to their CoA-esters as described in the text, and their fatty-acyl-groups transferred to CoA in the matrix by the concerted action of CPT 1, the acylcarnitine/carnitine exchange carrier and CPT (A) as described in the text. Medium-chain and short-chain fatty acids (Cg or less) diffuse directly into the matrix where they are converted to their acyl-CoA esters by a acyl-CoA synthase. The mechanism of p-oxidation is shown below (B). Each cycle of P-oxidation removes -CH2-CH2- as an acetyl unit until the fatty acids are completely converted to acetyl-CoA. The enzymes catalyzing each stage of P-oxidation have different but overlapping specificities. In muscle mitochondria, most acetyl-CoA is oxidized to CO2 and H2O by the citrate cycle (Figure 4) some is converted to acylcamitine by carnitine acetyltransferase (associated with the inner face of the inner membrane) and exported from the matrix. Some acetyl-CoA (if in excess) is hydrolyzed to acetate and CoASH by acetyl-CoA hydrolase in the matrix. Enzymes ...

The rate of mitochondrial oxidations and ATP synthesis is continually adjusted to the needs of the cell (see reviews by Brand and Murphy 1987 Brown, 1992). Physical activity and the nutritional and endocrine states determine which substrates are oxidized by skeletal muscle. Insulin increases the utilization of glucose by promoting its uptake by muscle and by decreasing the availability of free long-chain fatty acids, and of acetoacetate and 3-hydroxybutyrate formed by fatty acid oxidation in the liver, secondary to decreased lipolysis in adipose tissue. Product inhibition of pyruvate dehydrogenase by NADH and acetyl-CoA formed by fatty acid oxidation decreases glucose oxidation in muscle. 

The tricarboxylic acid cycle was therefore validated, having been tested not only in pigeon-breast muscle but also with brain, testis, liver, and kidney. The nature of the carbohydrate fragment entering the cycle was still uncertain. The possibility that pyruvate and oxaloacetate condensed to give a 7C derivative which would be decarboxy-lated to citrate, was dismissed partly because the postulated compound was oxidized at a very low rate. Further, work on the oxidation of fatty acids (see Chapter 7) had already established that a 2C fragment like acetate was produced by fatty acid oxidation, en route for carbon dioxide and water. It therefore seemed likely that a similar 2C compound might arise by decarboxylation of pyruvate, and thus condense with oxaloacetate. For some considerable time articles and textbooks referred to this unknown 2C compound as active acetate. ... 

Fatty acid oxidation occurs in mitochondria and peroxisomes in most tissues but quantitatively muscle is a major consumer of fat. Although carbohydrates and fatty acids may both be used as fuels for muscle contraction, fatty acids are more calorific... 

Fatty acid utilized by muscle may arise from storage triglycerides from either adipose tissue depot or from lipid stores within the muscle itself. Lipolysis of adipose triglyceride in response to hormonal stimulation liberates free fatty acids (see Section 9.6.2) which are transported through the bloodstream to the muscle bound to albumin. Because the enzymes of fatty acid oxidation are located within subcellular organelles (peroxisomes and mitochondria), there is also need for transport of the fatty acid within the muscle cell this is achieved by fatty acid binding proteins (FABPs). Finally, the fatty acid molecules must be translocated across the mitochondrial membranes into the matrix where their catabolism occurs. To achieve this transfer, the fatty acids must first be activated by formation of a coenzyme A derivative, fatty acyl CoA, in a reaction catalysed by acyl CoA synthetase. 

Figure 7.13 Physiological pathway for fatty acid oxidation. The pathway starts with the hormone-sensitive lipase in adipose tissue (the flux-generating step) and ends with the formation of acetyl-CoA in the various tissues. Acetyl-CoA is the substrate for the flux-generating enzyme, citrate synthase, for the Krebs cycle (Chapter 9). Heart, kidney and skeletal muscle are the major tissues for fatty acid oxidation but other tissues also oxidise them.

Fatty acids are released from adipose tissue into the bloodstream, from where they can be taken up and used by aerobic tissues, with the exception of brain and the intestine. In addition, an increase in the plasma fatty acid concentration is one factor that increases the rate of fatty acid oxidation by tissues. Flence, an increase in the mobilisation of fatty acid from adipose tissue is an immediate signal for tissues such as muscle, heart and kidney cortex to increase... 

The situation is, however, different in starvation. In this condition, it is the degradation of muscle protein that provides the amino acids for gluconeo-genesis, so that all the oxo-acids generated (except those for lysine and lencine) are nsed to synthesise the glucose required for oxidation by the brain. Hence, a process other than amino acid oxidation mnst generate the ATP required by gluconeogenesis. This process is fatty acid oxidation. 

As the duration of low-intensity exercise increases, the contribution of fat oxidation to ATP generation rises and parallels the reduced contribution of glycogen (Table 13.7). For very prolonged activities, when aU the muscle and fiver glycogen has been used, fatty acids become the only fuel available. However, fatty acid oxidation can generate ATP that no more than the rate provides about 60% of which... 

Figure 13.20 The use of glycogen and/or fatty acids during a prolonged running event (an ultramarathon). The distance of an ultramarathon is usually >50 miles. In the early part of the run, both glycogen and fatty acids are the fuels oxidised by the muscle. After several hours, glycogen is exhausted and fatty acids are the only fuel used. As fatty acid oxidation cannot provide more than about 60% of the ATP required for maximum power output, if the athlete is running at about 70 or 80% of the maximum, the output (i.e. the pace) must slow. Hence the rate of oxygen consumption (VO2) falls to about 60% of maximum (V02 ax), as shown in the Figure. The data on which the plot is based are from Davies Thompson (1979).

Malonyl-CoA inhibits fatty acid oxidation in muscle. Insulin increases the concentration of malonyl-CoA in muscle and so inhibits fatty acid oxidation. A fall in... 

Figure 16.1 The glucose/fatty add cycle. The dotted Lines represent regulation. Glucose in adipose tissue produces glycerol 3-phosphate which enhances esterification of fatty acids, so that less are available for release. The effect is, therefore, tantamount to inhibition of lipolysis. Fatty acid oxidation inhibits pyruvate dehydrogenase, phosphofructokinase and glucose transport in muscle (Chapters 6 and 7) (Randle et al. 1963).

Figure 16.2 Redprocal relationship between the changes in the concentrations of glucose and fatty adds in blood during starvation in adult humans. As the glucose concentration decreases, fatty acids are released from adipose tissue (for mechanisms see Figure 16.4). The dotted line is an estimate of what would occur if fatty acid oxidation did not inhibit glucose utilisation. Such a decrease occurs if fatty acid oxidation in muscle is decreased by specific inhibitors.

Figure 16.5 Effect of malonyl-CoA on the glucose/fatty acid cycle. Malonyl-CoA is an inhibitor of fatty acid oxidation, so that it decreases fatty acid oxidation in muscle and thus facilitates glucose utilisation (See Figure 7.14). Malonyl-CoA is formed from acetyl-CoA via the enzyme acetyl-CoA carboxylase, which is activated by insulin. Insulin therefore has three separate effects to stimulate glucose utilisation in muscle.

Initially the level of insulin decreases, favouring increased rates of lipolysis, fatty acid oxidation, muscle protein degradation, glycogenolysis and gluconeogenesis. It soon increases, however, as a result of insulin resistance, when the stimulation of the above processes will depend on the cytokine levels. For details of endocrine hormone effects, see Chapter 12. For details of cytokines see Chapter 17. 

The increased oxidation of fatty acids decreases the rate of glucose utilisation and oxidation by muscle, via the glucose/fatty acid cycle, which accounts for some of the insulin resistance in trauma. An additional factor may be the effect of cytokines on the insulin-signalling pathway in muscle. An increased rate of fatty acid oxidation in the liver increases the rate of ketone body production the ketones will be oxidised by the heart and skeletal muscle, which will further reduce glucose utilisation. This helps to conserve glucose for the immune and other cells. 

Gerhart-Hines, Z., Rodgers, J.T, Bare, 0 Lerin, C., Kim, S.H., Mostoslavsky, R., Alt, F.W., Wu, Z. and Puigserver, P. (2007) Metabolic control of muscle mitochondrial function and fatty acid oxidation through SIRTl/PGC-lalpha. The EMBO Journal, 26, 1913-1923. 

CN184 Plot. C., ]. F. Hocquette, ]. H. Veerkamp, D. Durand, and D. Bauchart. Effects of dietary coconut oil on fatty acid oxidation capacity of the liver, the heart and skeletal muscles in... 

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