Untypical Metabolic Adaptations in Spontaneously Hypertensive Rats to Free Running Wheel Activity Includes Uncoupling Protein-3 (UCP-3) and Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) Expression

Abstract

Obesity and hypertension are common risk factors for cardiovascular disease whereas an active lifestyle is considered as protective. However, the interaction between high physical activity and hypertension is less clear. Therefore, this study investigates the impact of high physical activity on the muscular and hepatic expression of glucose transporters (Glut), uncoupling proteins (UCPs), and proprotein convertase subtilisin/kexin type 9 (PCSK9) in spontaneously hypertensive rats (SHRs). Twenty-four female rats (12 normotensive rats and 12 SHRs) were divided into a sedentary control and an exercising group that had free access to running wheels at night for 10 months. Blood samples were taken and blood pressure was determined. The amount of visceral fat was semi-quantitatively analyzed and Musculus gastrocnemius, Musculus soleus, and the liver were excised. Acute effects of free running wheel activity were analyzed in 15 female SHRs that were sacrificed after 2 days of free running wheel activity. M. gastrocnemius and M. soleus differed in their mRNA expression of UCP-2, UCP-3, GLUT-4, and PCSK9. Hypertension was associated with lower levels of UCP-2 and PCSK9 mRNA in the M. gastrocnemius, but increased expression of GLUT-1 and GLUT-4 in the M. soleus. Exercise down-regulated UCP-3 in the M. soleus in both strains, in the M. gastrocnemius only in normotensives. In SHRs exercise downregulated the expression of UCP-2 in the M. soleus. Exercise increased the expression of GLUT-1 in the M. gastrocnemius in both strains, and that of GLUT-4 protein in the M. soleus, whereas it increased the muscle-specific expression of PCSK9 only in normotensive rats. Effects of exercise on the hepatic expression of cholesterol transporters were seen only in SHRs. As an acute response to exercise increased expressions of the myokine IL-6 and that of GLUT-1 were found in the muscles. This study, based on transcriptional adaptations in striated muscles and livers, shows that rats perform long-term metabolic adaptations when kept with increased physical activity. These adaptations are at least in part required to stabilize normal protein expression as protein turnover seems to be modified by exercise. However, normotensive and hypertensive rats differed in their responsiveness. Based on these results, a direct translation from normotensive to hypertensive rats is not possible. As genetic differences between normotensive humans and patients with essential hypertension are likely to be present as well, we would expect similar differences in humans that may impact recommendations for non-pharmacological interventions.

Effects of voluntary exercise on the expression of browning markers in visceral and subcutaneous fat tissue of normotensive and spontaneously hypertensive rats

“…Another group of rats had free excess to running wheels for 4 weeks with cessation for another 4 weeks and again access to running wheels (intermittent exercise; SHR-IR). Running distance, running time, kidney function, blood pressure, and adaptation to exercise in kidney and skeletal muscle were reported earlier for these the rats [10][11][12][13]. Briefly, running distance was 74 ± 33 km/week (Wistar) and 94 ± 16 km/week (SHR).…”

“…That was, however, not the case. It might be that 4 weeks of running performance interrupted by 4 weeks of resting periods was too long to indicate such an effect as we have previously shown that an increased expression of IL-6 in skeletal muscles, an indicator of increased myokine release, was significant after 2 days but not in the IR group [ 13 ].…”

“…Diastolic blood pressure was 80 ± 6 mmHg (Wistar) and 122 ± 10 mmHg (SHR) (see Ref. 13 for technical details).…”

Monoamine Oxidase A Contributes to Serotonin—But Not Norepinephrine-Dependent Damage of Rat Ventricular Myocytes

“…Samples from left ventricular tissue were used to quantify the expression of genes related to 5-HT metabolism or signaling. These samples were obtained from rats previously used for other studies as well [ 30 , 31 , 32 ]. For details of animal characteristics and blood pressure, please see [ 27 , 31 ].…”