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Review
. 2021 Nov;9(21):e15114.
doi: 10.14814/phy2.15114.

The pathophysiology of leg cramping during dialysis and the use of carnitine in its treatment

Akira Takahashi  1
Affiliations
Review

The pathophysiology of leg cramping during dialysis and the use of carnitine in its treatment

Akira Takahashi. Physiol Rep. 2021 Nov.

Abstract

Leg cramping is a common side effect of hemodialysis, and this is frequently treated by the administration of carnitine, but this is not effective in every patient. Alkalosis is a key component of the etiology of leg cramping during hemodialysis sessions. This is mediated through the binding of calcium ions to serum albumin, which causes hypocalcemia, and an increase in the release of calcium ions from the sarcoplasmic reticulum. Normally the calcium pump on the sarcoplasmic reticulum consumes ATP and quickly reuptakes the released calcium ions, which rapidly stops excessive muscle contractions. Thus, carnitine deficiency results in prolonged muscle contraction because of ATP depletion. However, during ATP production, carnitine is only involved up to the stage of acyl-CoA transport into mitochondria, and for the efficient generation of ATP, the subsequent metabolism of acyl-CoA is also important. For example, β-oxidation and the tricarboxylic acid cycle may be affected by a deficiency of water-soluble vitamins and the electron transport chain requires coenzyme Q10, but statins inhibit its production. The resulting accumulation of excess long-chain acyl-CoA in mitochondria inhibits enzymes involved in energy production. Thus, carnitine administration may be used more effectively if clinicians are aware of its specific physiologic roles.

Keywords: ATP; acyl coenzyme A; carnitine; coenzyme Q10; contraction alkalosis; leg cramping; muscle cramp.

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Conflict of interest statement

The author declares no conflict of interest.

Figures

FIGURE 1
FIGURE 1
The carnitine shuttle system. Carnitine is necessary for the transport of fatty acids into mitochondria, which is accomplished as part of the long‐chain fatty acid transport system, referred to as the carnitine circuit or carnitine shuttle, which also comprises several enzymes in the mitochondrial membrane, and plays an important role in energy production from fatty acids. Organic ion/carnitine transporter 2 (OCTN2) is expressed in cell membranes and has the effect of concentrating carnitine to 20–50 times its extracellular concentration. Free fatty acids are converted to acyl‐CoAs by long‐chain acyl‐CoA synthetase (ACS) on the outer mitochondrial membrane and then transported into the space between the outer and inner mitochondrial membranes. Here, a reaction between acyl‐CoA and carnitine occurs that is catalyzed by carnitine palmitoyltransferase I (CPT‐1) on the inside of the outer mitochondrial membrane, and the acylcarnitine generated is transported to the inner mitochondrial matrix by carnitine acylcarnitine translocase (CACT) on the inner mitochondrial membrane. The acylcarnitine is then broken down to liberate carnitine and long‐chain fatty acids by carnitine palmitoyltransferase 2 (CPT‐2) that is expressed inside the inner mitochondrial membrane, and the released fatty acids undergo β‐oxidation in the mitochondrial matrix to generate energy. Free carnitine then returns to the intermembrane space via CACT. Thus, free carnitine and acylcarnitine are transported in opposite directions, whether the movement of acylcarnitine is inward or outward. However, this circuit cannot operate if there is an absolute deficiency of free carnitine or if there is a shortage of free carnitine relative to the amount of acyl‐CoA (carnitine insufficiency) (Angelini et al., 1992). C, carnitine; ACS, acyl‐CoA synthetase; CPT, carnitine palmitoyltransferase, CoA, coenzyme A
FIGURE 2
FIGURE 2
Carnitine is necessary for the export of fatty acids from mitochondria. Free carnitine binds to the acyl group of acyl‐CoA to form acylcarnitine, and is excreted extracellularly. Acyl compounds are metabolic intermediates, but are cytotoxic when they accumulate in individuals with organic acid metabolism disorders. These cytotoxic effects are mediated through the inhibition of various mitochondrial enzymes. Under normal circumstances, free carnitine is used to remove excess acyl‐CoA from cells as the carnitine ester acylcarnitine, which is excreted in the urine. Therefore, free carnitine represents an endogenous means of preventing the deleterious effects of acyl compounds (Stumpf et al., 1985). ACS, acyl‐CoA synthetase; CPT, carnitine palmitoyltransferase
FIGURE 3
FIGURE 3
Controlling muscle spasms with carnitine. Alkalosis is involved in the etiology of muscle spasms, and contraction alkalosis is even more relevant for the leg cramping that occurs during the later stages of hemodialysis sessions. In general, alkalosis induces the binding of calcium ions to serum albumin, and therefore alkalosis causes hypocalcemia. Additionally, alkalosis makes it easier for calcium ions to be released from the sarcoplasmic reticulum of muscle cells, which leads to muscle cramping. The calcium pump on the sarcoplasmic reticulum consumes ATP and quickly reabsorbs the released calcium ions; therefore, muscle contractions are usually of short duration. However, in carnitine deficiency, muscle contractions are prolonged because of ATP depletion
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