Gioscia-Ryan 2015 Abstract MiPschool Greenville 2015

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Voluntary aerobic exercise increases stress resilience and improves mitochondrial health in arteries of old mice.


Gioscia-Ryan RA, Battson ML, Cuevas LM, Zigler MC, Seals DR (2015)

Event: MiPschool Greenville 2015

Age-related arterial endothelial dysfunction, characterized by a decline in endothelium-dependent dilation (EDD), is mediated largely by oxidative stress. Excessive levels of mitochondria-derived reactive oxygen species (mtROS), a hallmark of mitochondrial dysfunction, are an important contributor to tonic arterial oxidative stress-mediated suppression of EDD with aging [1]. In addition to baseline deficits in arterial function, aging may also be accompanied by reduced arterial resilience, i.e., the ability to withstand stress. Aging exacerbates the effects of common stressors such as a “Western”-style (high fat/high sugar) diet, hyperglycemia, and elevated low-density lipoprotein (LDL) cholesterol, such that the age- and stressor-associated impairments in arterial function are compounded [2]. However, whether declines in arterial mitochondrial health contribute to decreased resilience with aging is unknown. Aerobic exercise is a powerful intervention that restores baseline endothelial function with aging and improves mitochondrial health in many non-vascular tissues but the effects of exercise on arterial resilience and mitochondrial health with primary aging are unexplored. We tested the hypothesis that aging would be associated with reduced arterial mitochondrial health and impaired arterial resilience to acute stress, and that voluntary aerobic exercise initiated in late life would improve arterial mitochondrial health and increase resilience of aging arteries.

Young (5 mo) and old (25 mo) male C57BL/6 mice were randomly assigned to either a sedentary cage control group (young and old control [YC, n=11 and OC, n=12]) or a voluntary aerobic exercise group (young and old voluntary wheel running [YVR, n=10 and OVR, n=11] for 10 weeks. After 10 weeks, endothelial function was assessed in isolated carotid arteries as EDD in response to increasing doses of acetylcholine (ACh). Arterial resilience was determined as the change in EDD response with ACh alone versus following acute application of a mitochondrial stressor (rotenone 0.5 µM, 40 min [1]) or a simulated “Western Diet (WD)” stressor (8 mM glucose + 160 µM palmitate; 40 min intraluminal infusion). The contribution of mtROS to the “WD” stress was determined by assessing EDD with “WD” in the presence of the mitochondria-specific antioxidant MitoQ (1 µM) [3]. Arterial mtROS production was assessed in aortic segments via electron paramagnetic resonance with the mitochondrial superoxide-specific spin probe mitoTEMPO-H. Arterial protein markers of mitochondrial health (PGC-1α, SIRT-3, Fis-1 [TTC11]) were assessed by Western blotting (normalized to GAPDH).

Labels: MiParea: Exercise physiology;nutrition;life style  Pathology: Aging;senescence  Stress:Oxidative stress;RONS  Organism: Mouse  Tissue;cell: Endothelial;epithelial;mesothelial cell 

Event: Oral 


Dept Integrative Physiol, Univ Colorado Boulder, CO, USA. -

Abstract continued

As expected and in line with previous findings [2], exercise completely ameliorated age-related baseline arterial dysfunction (peak EDD (%): YC=89.2±1.8; YVR=93.5±2.3; OVR=88.7±2.2, all p<0.05 vs OC=66.1±4.1). Here, we extend this finding by demonstrating that exercise also improved arterial resilience to acute mitochondria-specific and simulated physiological (“WD”) stress [4] (Figure 1). Specifically, rotenone caused a significant further reduction in EDD in OC only, but not YC, YVR or OVR. Acute “WD” reduced EDD in YC and further impaired EDD in OC, whereas YVR and OVR were protected from this insult. Simultaneous application of MitoQ prevented the impairments induced by “WD,” indicating that the effects of this stressor were mediated by mtROS. The improvements in arterial resilience with voluntary aerobic exercise were accompanied by reduced arterial mtROS production (YC=1.0±.09; YVR=1.1±.11; OVR=0.82±.17, all p<0.05 vs. OC=1.4±0.2 AU) and normalization of age-related changes in arterial protein markers of mitochondrial health (PGC-1α (AU): YC=1.0±0.14; YVR=0.78±0.18; OVR=0.81±0.26, all p<0.05 vs. OC=0.45±0.09; SIRT-3 (AU): YC=1.0±0.30; YVR=0.79±0.47; OVR=1.05±0.62, all p<0.05 vs. OC=0.47±0.23; Fis-1 (AU): YC=1.0±0.32; YVR: 1.43±0.56; OVR=1.41±0.52, all p<0.09 vs. OC=1.96±0.64). Together, our results indicate that increased arterial susceptibility to acute stressors (featuring excess mtROS) with primary aging may be mediated by reduced arterial mitochondrial health. Importantly, voluntary aerobic exercise increases arterial resilience to stress, perhaps due to favorable arterial mitochondrial adaptations.

Figure 1

MiPschool2015Greenville Gioscia-Ryan Figure.jpg

References and acknowledgements

  1. Gioscia-Ryan RA, LaRocca TJ, Sindler AL, Zigler MC, Murphy MP, Seals DR (2014) Mitochondria-targeted antioxidant (MitoQ) ameliorates age-related arterial endothelial dyfunction. J Physiol 592:2549-61.
  2. Seals DR (2014) Edward F. Adolph distinguished lecture: The remarkable anti-aging effects of aerobic exercise on systemic arteries. J Appl Physiol 117:425-39.
  3. Murphy MP, Smith RAJ (2007) Targeting antioxidants to mitochondria by conjugation to lipophilic cations. Annu Rev Pharmacol Toxicol 47:629-56.
  4. Gioscia-Ryan RA, Battson ML, Sindler AL, Cuevas LM, Zigler MC, Seals DR (2014) Aerobic exercise increases stress resistance in arteries of old mice. FASEB J 28:1106.9.

Supported by NIH AG013038, AG000279, HL107120, F31AG047784.