TRPV1 (Transient Receptor Potential Vanilloid 1) Sensitization of Skeletal Muscle Afferents in Type 2 Diabetic Rats With Hyperglycemia

Abstract

The blood pressure response to exercise is exaggerated in type 2 diabetes (T2D). However, the underlying mechanisms remain unclear. It is hypothesized that one mechanism mediating the potentiated cardiovascular response in T2D is the sensitization of chemically sensitive afferent neurons by activation of metaboreceptors. To test this hypothesis, we examined TRPV1 (transient receptor potential vanilloid 1)-induced cardiovascular responses in vivo and muscle afferent discharge ex vivo in T2D rats. Additionally, TRPV1 and PKC (protein kinase C) protein levels in dorsal root ganglia subserving skeletal muscle were assessed. For 14 to 16 weeks, Sprague-Dawley rats were given either a normal diet (control) or a high-fat diet in combination with a low dose (35 and 25 mg/kg) of streptozotocin (T2D). Administration of capsaicin, TRPV1 agonist, in hindlimb evoked significantly greater increases in mean arterial pressure and renal sympathetic nerve activity in decerebrated T2D than control. In a muscle-nerve preparation, the discharge to capsaicin exposure in group IV afferents isolated from T2D was likewise significantly augmented at a magnitude that was proportional to glucose concentration. Moreover, the discharge to capsaicin was potentiated by acute exposure of group IV afferents to a high-glucose environment. T2D showed significantly increased phospholyrated-TRPV1 and -PKCα levels in dorsal root ganglia neurons as compared with control. These findings suggest that group IV muscle afferents are sensitized by PKC-induced TRPV1 overactivity in early stage T2D with hyperglycemia and, thereby, may contribute to the potentiated circulatory response to TRPV1 activation in the disease.

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

“…2016; Ishizawa et al . 2021), which may increase the risk for adverse cardiovascular events and stroke during or immediately after a bout of exercise (Hoberg et al . 1990; Mittleman et al .…”

“…Second, TRPV1, located on thin-fibre muscle afferents, has been suggested to be a key receptor contributing to muscle metaboreflex-induced increases in blood pressure (Smith et al 2010;Mizuno et al 2011;Li & Garry, 2020). Recent animal and human studies have shown that the chemically sensitive muscle metaboreflex is exaggerated in type 2 diabetes mellitus (Holwerda et al 2016;Ishizawa et al 2021), which may increase risk for adverse cardiovascular events and stroke during or immediately after a bout of exercise (Hoberg et al 1990;Mittleman et al 1993). Because hyperinsulinaemia is a common characteristic of individuals in an insulin-resistant state, findings from the current investigation might explain the mechanism underlying the exaggerated skeletal muscle metaboreflex previously demonstrated in type 2 diabetes.…”

Hypoglycemic Effect of Electroacupuncture at ST25 Through Neural Regulation of the Pancreatic Intrinsic Nervous System

“…The use of a combination of a high-fat diet (HFD) and a low dose of streptozotocin (STZ) has been shown to effectively establish a rat model of diabetes that mimics the metabolic characteristics of common T2DM in humans [ 33 ]. Seven-week-old Sprague Dawley (SD) rats were supplied by the model animal research center of the Nanjing University of Chinese Medicine (No.…”

Exaggerated exercise pressor reflex in male UC Davis type 2 diabetic rats is due to the pathophysiology of the disease and not aging

“…The sensory arm of the reflex comprises a mechanically sensitive component conducted predominantly through thinly myelinated group III muscle afferents, namely the mechanoreflex; and a metabolically sensitive component conducted predominantly through unmyelinated group IV muscle afferents, namely the metaboreflex ( Kaufman et al, 1983 ). Research has shown that both the mechanoreflex and the metaboreflex are exaggerated in T2DM ( Holwerda et al, 2016 ; Grotle et al, 2019 ; Kim et al, 2019 ; Ishizawa et al, 2021 ). For example, passive tendon stretch, which activates the mechanoreflex, evoked significantly higher BP and HR responses in T2DM rats compared to their healthy control ( Grotle et al, 2019 ).…”

“…For example, passive tendon stretch, which activates the mechanoreflex, evoked significantly higher BP and HR responses in T2DM rats compared to their healthy control ( Grotle et al, 2019 ). In addition, the pressor, cardioaccelerator, and sympathetic responses are significantly higher in response to capsaicin, which activates the metaboreflex, in T2DM rats compared to their healthy controls ( Ishizawa et al, 2021 ). These studies strongly support that the exercise pressor reflex is exaggerated in T2DM ( Holwerda et al, 2016 ; Grotle et al, 2019 ; Kim et al, 2019 ; Vranish et al, 2020 ).…”