ATP releasing channels and the ameliorative effects of high intensity interval training on diabetic heart: a multifaceted analysis

Abstract

Type 2 diabetes (T2D) can cause severe cardiac complications at functional, histologic and molecular levels. These pathological complications could be mediated by ATP-releasing channels such as Panx1 and ATP receptors, in particular P2X7. The aim of our study was to investigate the effect of high-intensity interval training (HIIT) on T2D-induced cardiac complications at the functional, histopathological and molecular levels, with a particular focus on ATP-releasing channels. 48 male Wistar rats at the age of 8 weeks were randomly allocated into four groups: control (Con), Diabetes (T2D), Training (TR), and Diabetes + Training (T2D + TR). T2D was induced by a high-fat diet plus a low dose (35 mg/kg) of STZ administration. Rats in the TR and T2D + TR groups underwent an 8-weeks training program involving intervals ranging from 80 to 100% of their maximum running speed (Vmax), with 4-10 intervals per session. Protein expression of Interleukin 1β (IL1β), Interleukin 10 (IL-10), Pannexin 1 (Panx1), P2X7R (purinergic P2X receptor 7), NLRP1 (NLR Family Pyrin Domain Containing 1), BAX, and Bcl2 were measured in the heart tissue. Additionally, we assessed heart function, histopathological changes, as well as insulin resistance using the homeostasis model assessment of insulin resistance (HOMA-IR). In contrast to the T2D group, HIIT led to increased protein expression of Bcl2 and IL-10 in the heart. It also resulted in improvements in systolic and diastolic blood pressures, heart rate, ± dp/dt (maximum and minimum changes in left ventricular pressure), while reducing protein expression of IL-1β, Panx1, P2X7R, NLRP1, and BAX levels in the heart. Furthermore, left ventricular diastolic pressure (LVDP) was reduced (P ≤ 0.05). Moreover, heart lesion scores increased with T2D but decreased with HIIT, along with a reduction in fibrosis percentage (P ≤ 0.05). The results of this study suggest that the cardioprotective effects of HIIT on the diabetic heart may be mediated by the modulation of ATP-releasing channels. This modulation may lead to a reduction in inflammation and apoptosis, improve cardiac function, and attenuate cardiac injury and fibrosis.

Keywords: ATP-releasing channels; HIIT; Inflammation; Type 2 diabetes.

Figure 1

The effects of T2D and HIIT on fasting blood glucose (A) before starting the intervention (month 0), after diabetes induction (2 months of high-fat diet and STZ injection) (month 2), and 48 h after the last training session (month 4) in experimental groups and HOMA-IR (B) (mean ± SD). (n = 7 in each group). FBG: Fasting blood glucose, Con: control, T2D: Type 2 diabetic (STZ injected), TR: training only, and T2D + TR: Type 2 diabetic + Training. ***P < 0.001 & **P < 0.01 compared to the Con group. ###P < 0.001 compared to the T2D group. $$P < 0.01 compared to the TR group.

Figure 2

The effects of T2D and HIIT on Left ventricular end-diastolic pressure (LVEDP) (A), systolic (B), diastolic (C) pressures, and Heart rate (D) in experimental groups (n = 7 in each group). Con: control, T2D: Type 2 diabetic, TR: Training, and T2D + Ex: Type 2 diabetic + Training.**P < 0.01 & ***P < 0.001 compared to the Con group. ###P < 0.001 & ##P < 0.01 compared to the T2D group. $ P < 0.05 & $$$ P < 0.001 compared to the TR group.

Figure 3

The effects of T2D and HIIT on Positive dP/dt max (+ dP/dt max) and negative dP/dt max (− dP/dt max) in experimental groups (n = 7 in each group). Con: control, T2D: Type 2 diabetic, TR: Training, and T2D + TR: Type 2 diabetic + Training. *P < 0.05 compared to the Con group. # P < 0.05 & ## P < 0.01 compared to the T2D group.

Figure 4

The effects of T2D and HIIT on Heart protein levels of Panx 1 (A), P2X7R (B), and NLRP1 (C) (mean ± SD) in experimental groups (n = 7 in each group). The blot image in each figure is a representative of seven protein extracts. Panx 1: pannexin 1, Con: control, T2D: Type 2 diabetic, TR: Training, and T2D + TR: Type 2 diabetic + Training. *P < 0.05 & ***P < 0.001 & **P < 0.01 compared to the Con group. # P < 0.05 & ### P < 0.001 compared to the T2D group. $$ P < 0.01 compared to the TR group.

Figure 5

The effects of T2D and HIIT on Heart protein levels of BAX (A) and Bcl2 (B) (mean ± SD) in experimental groups (n = 7 in each group). The blot image in each figure is a representative of seven protein extracts. Con: control, T2D: Type 2 diabetic, TR: Training, and T2D + TR: Type 2 diabetic + Training. ***P < 0.001 & *P < 0.05 compared to the Con group. ## P < 0.01 & ### P < 0.001 compared to the T2D group. $$$ P < 0.001 compared to the TR group.

Figure 6

The effects of T2D and HIIT on Heart levels of IL1β (A) and IL-10 (B) (mean ± SD) in experimental groups (n = 7 in each group). Con: control, T2D: Type 2 diabetic, TR: Training, and T2D + TR: Type 2 diabetic + Training. ***P < 0.001 & *P < 0.05 compared to the Con group. # P < 0.05 & ### P < 0.001 compared to the T2D group.

Figure 7

The effects of T2D and HIIT on heart injury. Micrographs of the heart stained with H&E. Data are presented as mean ± SD. Con: A: control; B: T2D C: TR; D: T2D + TR. Co: control, T2D: Type 2 diabetic, TR: Training, and T2D + TR: Type 2 diabetic + Training. Black arrows indicate congestion and blue arrows indicate hypertrophy. ***P < 0.001 compared to the Con group. ## P < 0.01 compared to the T2D group.

Figure 8

The effects of T2D and HIIT on heart fibrosis. Micrographs of the heart stained with Masson trichrome showed heart fibrosis. Data are presented as mean ± SD. Con: A: control; B: T2D C: TR; D: T2D + TR. Co: control, T2D: Type 2 diabetic, TR: Training, and T2D + TR: Type 2 diabetic + Training. Black arrows indicate fibrotic changes. ***P < 0.001 & **P < 0.01 compared to the Con group. ### P < 0.001 compared to the T2D group. $$$ P < 0.001 compared to the TR group.

Figure 9

HIIT could improve diabetic hearts through modulation of ATP-releasing channel expression, inflammation, and apoptosis.