High intensity exercise improves the metabolic syndrome in an aged murine model, but it abrogates the vascular function improvement induced by moderate exercise
Authors: Meza-Ramos A , Alcarraz A , Lazo-Rodriguez M , Banon-Maneus E , Rovira J , Ramirez-Bajo M J , Ventura-Aguiar P , Mont L , Batlle M , Guasch E 
Published: October 2022

Abstract

Introduction
Compelling evidence supports that regular moderate exercise has a positive impact on cardiovascular disease (CVD) incidence and prognosis [1]. Nevertheless, emerging clinician and experimental data in healthy individuals suggests that long-term, high-intensity endurance exercise might increase vascular stiffness and enhance coronary calcification [2,3]. In patients with CV risk factors, it has been hypothesized that the beneficial effects of strenuous exercise on risk factors could outweigh its deleterious effects, but this remains unproven [4].

Purpose
To analyze how increasing doses of exercise impinge on the vascular system in a murine model of aged rats with metabolic syndrome and kidney disease.

Methods
Seven-week-old male Zucker obese rats, a metabolic syndrome model, were subjected to left nephrectomy. At 26 weeks of age, rats were assigned to a sedentary (SED), moderate intensity (MOD, 15 cm/s, 40 min/day), or high intensity (INT, 25 cm/s, 60 min/day) group, and trained 5 days/week for 10 weeks. An echocardiogram and a glucose tolerance test were performed 24 hours after the last training bout. At sacrifice, vascular reactivity was assayed in the descending thoracic aorta, and EC50 calculated for every experiment. Expression of oxidant and antioxidant mRNA markers was analyzed in thoracic perivascular adipose tissue (tPVAT). Cytokines levels (TNFα, IL10, IL6, Selectin, ICAM1 and Adiponectin) were analyzed in plasma samples.

Results
Rats in the INT group had a significantly lower body weight (10.99±0.35 g/mm vs 12.23±0.58 g/mm) and a higher heart weight (32.44±0.72 mg/mm vs 31.28±0.78 mg/mm), indexed by tibia length, than the SED group. Both MOD and INT exercise improved glucose tolerance compared with SED (Fig 1a). On echocardiography, INT rats presented with LV septum hypertrophy and dilation, mildly reduced ejection fraction and fractional shortening compared with SED. Aortic diameter was also increased in the INT group (3.62±0.11 mm vs 3.25±0.13 mm). In vascular reactivity assays, the MOD group showed improved endothelial function, indicated by a larger carbachol-induced relaxation than SED and INT (Fig. 1b). However, MOD and INT were no longer different after adding the antioxidant Tempol (Fig1c). No differences were found in tunica media fibrosis amongst the groups (19.12±0.45%; 26.97±2.52%; 25.98±2.14%). In tPVAT, the mRNA expression of prooxidants (NOX2, p47) was higher, and antioxidant markers (SOD2, GCH1) was lower in the INT group than MOD and SED (Fig. 2). TNFα levels were higher in plasma of INT rats than SED.

Conclusion
In a rodent model, both intense and moderate exercise improved the CV risk profile, but only moderate training improved vascular function. Oxidative stress may, at least partially, account for the lack of benefits of intensive exercise. Our results suggest that the deleterious effects of strenuous physical activity could persist even in individuals with CV risk factor.

Funding Acknowledgement
Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Fondo de Investigaciόn Sanitaria (FIS), Instituto de Salud Carlos III