Hyperpolarized shifts in the voltage dependence of fast inactivation of Na_v1.4 and Na_v1.5 in a rat model of critical illness myopathy

Abstract

Critical illness myopathy is a disorder in which skeletal muscle becomes electrically inexcitable. We previously demonstrated that a shift in the voltage dependence of fast inactivation of sodium currents contributes to inexcitability of affected fibres in an animal model of critical illness myopathy in which denervated rat skeletal muscle is treated with corticosteroids (steroid-denervated; SD). In the current study we examined whether expression of Na v 1.5 contributes to the altered voltage dependence of sodium channel inactivation in SD muscle. We used TTX and µ-conotoxin GIIIB to selectively block Na v 1.4 in SD muscle and found that the level of Na v 1.5 did not correlate closely with the shift in fast inactivation. Surprisingly, we found that the voltage dependence of inactivation of Na v 1.4 was similar to that of Na v 1.5 in skeletal muscle in vivo. In severely affected fibres, inactivation of both Na v 1.4 and Na v 1.5 was shifted towards hyperpolarized potentials. We examined the role of denervation and steroid treatment in the shift of the voltage dependence of inactivation and found that both denervation and steroid treatment contribute to the shift in inactivation. Our results suggest that modulation of the voltage dependence of inactivation of both Na v 1.4 and Na v 1.5 in vivo contributes to loss of electrical excitability in SD muscle.

Inactivation of sodium channels underlies reversible neuropathy during critical illness in rats

“…Both reduced channel number and increased fast inactivation of channels occur in muscle in CIM (29,30,34). If reduction in channel number is the cause of reduced excitability, relief of sodium channel inactivation should not greatly increase action potential amplitude.…”

“…In the CIM studies, we used voltage clamp techniques to directly study sodium currents in isolated muscle fibers and found that reduced numbers of channels did not fully account for the differences in excitability between severely affected and mildly affected muscle fibers (29). Instead, a hyperpolarized shift in the voltage dependence of sodium channel inactivation was the principal cause of reduced excitability (29,30,34). The hyperpolarized shift increased inactivation of sodium channels and reduced the number of channels available to open during action potentials.…”

Mechanisms of Neuromuscular Dysfunction in Critical Illness

“…Thus upregulation of Nav1.5 sodium channels could explain the presence of more inactivated sodium channels and hence reduced action potential generation, inexcitability and the clinical manifestation of weakness. However, although Nav1.5 sodium channels were present in SD muscle, they do not account for the alteration in sodium channel regulation [43,60]. This finding demonstrated that the primary cause of the loss of excitability of SD fibers is an alteration in the regulation of Nav1.4 sodium channels instead of the new expression of Nav1.5 channels.…”

C2C12 skeletal muscle cells adopt cardiac-like sodium current properties in a cardiac cell environment

“…A similar shift can be observed in our data (Table 2), consistent with an increased Na v 1.5 channel fraction in cardiac-conditioned versus control cells and the highest Na v 1.5 channel fraction in TTX-treated conditioned cells. Moreover, a mixed population of Na v 1.4 and Na v 1.5 channels should also reduce the slope of the voltage dependence of inactivation (8). Indeed, this was the case for both fast and slow inactivation in cardiacconditioned compared with control cells (compare K values in Table 2).…”