Skeletal Muscle Reflex–Induced Sympathetic Dysregulation and Sensitization of Muscle Afferents in Type 1 Diabetic Rats

Abstract

The blood pressure response to exercise is exaggerated in the type 1 diabetes mellitus (T1DM). An overactive exercise pressor reflex (EPR) contributes to the potentiated pressor response. However, the mechanism(s) underlying this abnormal EPR activity remains unclear. This study tested the hypothesis that the heightened blood pressure response to exercise in T1DM is mediated by EPR-induced sympathetic overactivity. Additionally, the study examined whether the single muscle afferents are sensitized by PKC (protein kinase C) activation in this disease. Sprague-Dawley rats were intraperitoneally administered either 50 mg/kg streptozotocin (T1DM) or saline (control). At 1 to 3 weeks after administration, renal sympathetic nerve activity and mean arterial pressure responses to activation of the EPR, mechanoreflex, and metaboreflex were measured in decerebrate animals. Action potential responses to mechanical and chemical stimulation were determined in group IV afferents with pPKCα (phosphorylated-PKCα) levels assessed in dorsal root ganglia. Compared with control, EPR (58±18 versus 96±33%; P <0.05), mechanoreflex (21±13 versus 51±20%; P <0.05), and metaboreflex (40±20 versus 88±39%; P <0.01) activation in T1DM rats evoked significant increases in renal sympathetic nerve activity as well as mean arterial pressure. The response of group IV afferents to mechanical (18±24 versus 61±45 spikes; P <0.01) and chemical (0.3±0.4 versus 1.6±0.8 Hz; P <0.01) stimuli were significantly greater in T1DM than control. T1DM rats showed markedly increased pPKCα levels in dorsal root ganglia compared with control. These data suggest that in T1DM, abnormally muscle reflex-evoked increases in sympathetic activity mediate exaggerations in blood pressure. Further, sensitization of muscle afferents, potentially via PKC activation, may contribute to this abnormal circulatory responsiveness.

Recent advances in exercise pressor reflex function in health and disease

“…Grotle et al (Grotle et al, 2017) were the first to show that untreated T1DM results in an exaggerated reflex pressor response to electrically induced static exercise in the early stage of the disease (Figure 8). Recently, another study extended these findings and showed that short-term T1DM leads to exaggerated sympathetic responsiveness to static muscle contraction, in part, due to the sensitization of group IV afferents (Ishizawa et al, 2020).…”

“…However, the specific channels and receptors involved are not well understood. Recently, a study showed that T1DM leads to increased sensitization of group IV afferents in vitro, potentially due to increased activity of PKC signaling (Ishizawa et al, 2020). Emerging evidence also supports a role of mechanically gated Piezo channels (Eijkelkamp et al, 2013;Grotle et al, 2019b;Szczot et al, 2018).…”

“…Furthermore, the pressor responses to both tendon stretch (Grotle et al, 2019b;Ishizawa et al, 2020) and local injection of capsaicin (Ishizawa et al, 2020) into the hindlimb vasculature are likewise exaggerated, suggesting that short-term T1DM alters the expression of the mechanoreflex and the metaboreflex. In contrast, the reflex pressor response to static muscle contraction became attenuated towards the later stage of the disease (Grotle et al, 2017), suggesting that the expression of the reflex may change as a result of the progression of the disease.…”

Insulin potentiates the response to capsaicin in dorsal root ganglion neurons in vitro and muscle afferents ex vivo in normal healthy rodents

“…Fifty rats (11 ± 3 weeks and BW: 358 ± 74 g) were used. These recordings were obtained using methods previously reported (Hotta et al 2015(Hotta et al , 2019aIshizawa et al 2020). We isolated the extensor digitorum longus (EDL) muscle along with the common peroneal nerve in a test chamber containing warmed modified Krebs-Henseleit solution (Krebs-buffer solution) superfused approximately at 34°C and pH 7.4.…”

“…After we identified a single group III or IV afferent fibre and its receptive field, we locally superfused 1 μM CAP (Sigma and Wako) for 30 s over the receptive field through a 3 mm-diameter metal tube as described previously (Taguchi et al 2005;Hotta et al 2015Hotta et al , 2019bIshizawa et al 2020). We placed the opening of the tube as near to the receptive field as possible while still leaving space for the solution to flow to minimize dilution (Taguchi et al 2005).…”