Myopathy of Critical Illness and Acetylcholine Receptors

Critical illnesses (see Chapter 75 and Chapter 76 ) such as sepsis, trauma, and burns induce functional and pharmacologic aberrations at the skeletal muscle, similar to that seen with upper or lower motor neuron injuries. The aberrant pharmacologic responses consist of a hyperkalemic response to succinylcholine and resistance to nondepolarizers.^{[1] [2]} The important functional change in muscle associated with critical illness is muscle weakness, resulting in hypoventilation, dependence on respirators, and decreased mobilization.^{[70] [71]} The pathognomic biochemical feature in all of these critical illnesses is the upregulation of acetylcholine receptors with expression of the immature (γ-subunit) isoform of receptors.^{[60] [61] [65] [66]}

The immature isoform has different electrophysiologic characteristics from those of the mature form, including prolonged open-channel time. In some clinical conditions, the presence of a prolonged open-channel time (due to congenital mutations in the receptor) is associated with muscle weakness.^{[37] [72] [73]} These conditions present as progressive muscle weaknesses and impaired neuromuscular transmission without overt degeneration of the motor end plate. The receptor numbers typically are not significantly reduced. In all of these congenital conditions with prolonged open-channel time, there is delayed closure of the acetylcholine receptor ion channel. This leads to increased calcium load into the cytosol, progressive widening, and accumulation of debris in the synaptic cleft, resulting in reduced efficiency of released neurotransmitter and reduced safety factor. In the pathologic state of burns, sepsis, and trauma, in which muscle weakness is a concomitant finding, the expression of the immature isoform at the perijunctional membrane may have a role in muscle weakness. The presence of immature isoform can lead to prolonged open-channel time.^[25] Whether these immature receptors play a role in the myopathy by this mechanism is unclear. The expression of the immature isoform may decrease the number of mature isoforms, a situation akin to myasthenia gravis, in which the mature receptor number at the junction is decreased.

In mice, deletion of the mature epsilon-subunit-containing receptors causes muscle weakness, despite the expression of immature receptors at the postjunctional membrane.^[74] When there is de novo expression of immature isoforms of the receptor containing the γ-subunit, signaling through receptor tyrosine kinases or through growth factors (e.g., insulin) seems to be impaired. ^{[62] [63] [64]} Decreased signaling of growth factors such as agrin and ARIA may account for the dispersion of the acetylcholine receptors from the junctional area to areas throughout the muscle membrane with concomitant expression of the immature isoform of receptor, even in the junctional area.^[75] These changes may play a role in the inefficient neurotransmission. The deficiency or absence of growth factor signaling (by means of insulin) leads to decreased anabolism of protein and enhanced muscle protein breakdown, including apoptosis, resulting in the loss of contractile elements. Apoptosis occurring in cardiac muscle contributes significantly to myocardial dysfunction.^[76] The loss of muscle mass from apoptosis and decreased protein synthesis due to the decreased anabolic effect of insulin and other growth factors^{[77] [78]} may compound the skeletal muscle weakness related to ineffective neurotransmission related to expression of immature receptor. Signaling through receptor kinases and its effects on acetylcholine expression and apoptosis are intense areas of research by many groups. Correction of the altered signaling mechanism may reverse the expression of the immature to mature isoform, attenuate the loss of muscle mass due to apoptosis in muscle, and correct the muscle weakness associated with critical illness.