Responses to Mechanical and Chemical Stimuli are Augmented by Insulin Administration in Neurons Innervating Skeletal Muscle
Authors: Hotta Norio , Katanosaka Kimiaki , Mizumura Kazue , Ishizawa Rie , Mitchell Jere H , Smith Scott A , Mizuno Masaki 
Published: June 2021

Hyperinsulinemia is known to activate the sympathetic nervous system, but the underlying mechanism remains to be elucidated. Mechanical or chemical stimuli to skeletal muscle induce sympathoexcitation via group III and group IV thin‐fiber afferents. Evidence suggests that insulin both facilitates translocation of molecular candidates for mechano‐gated channels and activates transient receptor potential vanilloid 1 (TRPV1) channels associated with these afferent fibers. We therefore hypothesized that insulin potentiates neural responsiveness to mechanical and chemical stimuli in thin‐fiber afferents and the dorsal root ganglia (DRG) that sub‐serve these neurons in skeletal muscle.PURPOSEWe investigated the effects of insulin administration on whole‐cell current responses to mechanical/chemical stimuli in DRG neurons of normal healthy mice. Further, we examined the impact of insulin on the action potential response to mechanical/chemical stimulation in thin‐fiber muscle afferents of normal healthy rats.METHODSWe performed whole cell patch‐clamp recordings using cultured mice DRG neurons. Mechanical stimuli to the cell surface was applied using a stimulation probe with resultant mechanically activated (MA) currents recorded. DRG neurons were also exposed to 1μM capsaicin. Using a rat muscle‐nerve preparation in vitro, we applied 1) a ramp‐shaped mechanical stimulation and 2) a 1μM capsaicin stimulation to the neuron's receptive field and measured the elicited action potential utilizing single‐fiber recordings.RESULTSIn cultured DRG neurons, insulin (500 mU) reduced mechanical threshold from 3.6 ± 0.4 to 2.6 ± 0.3 steps (n=17, P<0.05) and increased MA current from −93±12 to −190±43 pA (n=16, P<0.05). These changes were blocked by pretreatment with the insulin receptor inhibitor GSK1838705. Likewise, the total charge transfer induced by capsaicin activated current (fold change from baseline) was significantly higher after insulin administration (3.3±1.2, n=5) than that of control (0.5±0.2, n=6). Again, this difference was prevented by pretreatment with GSK1838705. In the muscle‐nerve preparation, the mechanical threshold of thin‐fiber muscle afferents was significantly decreased 10 min after insulin injection (500 mU) from 66±16 to 28±12 mN (n=10, P<0.05). This decrease was eliminated by insulin receptor blockade via GSK1838705. Insulin administration also significantly increased the response magnitude to 1μM capsaicin (from 0.05±0.08 Hz before insulin to 0.70±0.40 Hz after insulin, n=5, P<0.05).CONCLUSIONSThe data demonstrate that insulin sensitizes thin fiber afferents and DRG neurons innervating skeletal muscle. Further, these findings suggest that hyperinsulinemia may induce sympathoexcitation via augmentations in the responsiveness of mechano‐gated channels and TRPV1 receptors on skeletal muscle thin‐fiber afferents.Support or Funding InformationJSPS KAKENHI JP17K01769 and Southwestern School of Health Professions Interdisciplinary Research Grant ProgramThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.