Lifelong physical activity attenuates age- and Western-style diet-related declines in physical function and adverse changes in skeletal muscle mass and inflammation.

It is unknown if consumption of a Western diet (WD; high-fat/sucrose), versus a non-WD (healthy diet), accelerates declines in physical function over the adult lifespan, and whether regular voluntary activity attenuates age- and WD-associated declines in function. Accordingly, we studied 4 cohorts of mice that consumed either normal chow [NC] or WD with or without access (sedentary, Sed) to voluntary wheel running [VWR] beginning at 3 mo of age. We assessed coordination, grip strength and endurance every 6 mo throughout life, and measured skeletal muscle mass and inflammation at 3 pre-determined ages (6-7, 13-14 and 19-20 mo). Age-related declines (% change 3-18 mo) in physical function were accelerated in WD-Sed versus NC-Sed (coordination: +47 ± 5%; grip strength: +18 ± 2%; endurance: +32 ± 5%; all p < 0.05). VWR attenuated declines in physical function within diet group (coordination: -31 ± 3% with WD-VWR; -18 ± 2% with NC-VWR; grip strength: -26 ± 2% with WD-VWR; -24 ± 2% with NC-VWR; endurance: -48 ± 4% with WD-VWR; -23 ± 6% with NC-VWR; all p < 0.05). Skeletal muscle mass loss and pro-inflammatory cytokine abundance were exacerbated by WD throughout life (mass: NC-Sed [-]7-28%, WD-Sed [-]17-40%; inflammation: NC-Sed [+]40-65%, WD-Sed [+]40-84%, all p < 0.05 versus NC-Sed), and attenuated by VWR (mass: NC-VWR, [-]0-10%, WD-VWR [-]0-10%; inflammation: NC-VWR [+]0-30%, WD-VWR [+]0-42%, all p < 0.05 versus diet-matched Sed group). Our results depict the temporal impairment of physical function over the lifespan in mice, acceleration of dysfunction with WD, the protective effects of voluntary exercise, and the potential associations with skeletal muscle mass and inflammation.

Clayton ZS ，Gioscia-Ryan RA ，Justice JN ，Lubieniecki KL ，Hutton DA ，Rossman MJ ，Zigler MC ，Seals DR ... -  《-》

Lifelong voluntary aerobic exercise prevents age- and Western diet- induced vascular dysfunction, mitochondrial oxidative stress and inflammation in mice.

The results of the present study establish the temporal pattern of age-related vascular dysfunction across the adult lifespan in sedentary mice consuming a non-Western diet, and the underlying mechanisms The results demonstrate that consuming a Western diet accelerates and exacerbates vascular ageing across the lifespan in sedentary mice They also show that lifelong voluntary aerobic exercise has remarkable protective effects on vascular function throughout the lifespan, in the setting of ageing alone, as well as ageing compounded by Western diet consumption Overall, the results indicate that amelioration of mitochondrial oxidative stress and inflammation are key mechanisms underlying the voluntary aerobic exercise-associated preservation of vascular function across the lifespan in both the presence and absence of a Western dietary pattern ABSTRACT: Advancing age is the major risk factor for cardiovascular diseases, driven largely by vascular endothelial dysfunction (impaired endothelium-dependent dilatation, EDD) and aortic stiffening (increased aortic pulse wave velocity, aPWV). In humans, vascular ageing occurs in the presence of differences in diet and physical activity, but the interactive effects of these factors are unknown. We assessed carotid artery EDD and aPWV across the lifespan in mice consuming standard (normal) low-fat chow (NC) or a high-fat/high-sucrose Western diet (WD) in the absence (sedentary, SED) or presence (voluntary wheel running, VWR) of aerobic exercise. Ageing impaired nitric oxide-mediated EDD (peak EDD 88 ± 12% 6 months P = 0.003 vs. 59 ± 9% 27 months NC-SED), which was accelerated by WD (60 ± 18% 6 months WD-SED). In NC mice, aPWV increased 32% with age (423 ± 13 cm/s at 24 months P < 0.001 vs. 321 ± 12 cm/s at 6 months) and absolute values were an additional ∼10% higher at any age in WD mice (P = 0.042 vs. NC-SED). Increases in aPWV with age in NC and WD mice were associated with 30-65% increases in aortic intrinsic wall stiffness (6 vs. 19-27 months, P = 0.007). Lifelong aerobic exercise prevented age- and WD-related vascular dysfunction across the lifespan, and this protection appeared to be mediated by mitigation of vascular mitochondrial oxidative stress and inflammation. Our results depict the temporal impairment of vascular function over the lifespan in mice, acceleration and exacerbation of that dysfunction with WD consumption, the remarkable protective effects of voluntary aerobic exercise, and the underlying mechanisms.

Gioscia-Ryan RA ，Clayton ZS ，Zigler MC ，Richey JJ ，Cuevas LM ，Rossman MJ ，Battson ML ，Ziemba BP ，Hutton DA ，VanDongen NS ，Seals DR ... -  《-》

Translational machinery of mitochondrial mRNA is promoted by physical activity in Western diet-induced obese mice.

Mitochondria-encoded proteins are necessary for oxidative phosphorylation; however, no report has examined how physical activity (PA) and obesity affect mitochondrial mRNA translation machinery. Our purpose was to determine whether Western diet (WD)-induced obesity and voluntary wheel running (VWR) impact mitochondrial mRNA translation machinery and whether expression of this machinery is dictated by oxidative phenotype. Obesity was induced with 8-wk WD feeding, and in the final 4 wks, half of mice were allowed VWR. Mitochondrial mRNA translation machinery including initiation factors (mtIF2/3), elongation factor Tu (TUFM) and translational activator (TACO1), and mitochondria-encoded proteins (CytB and ND4) was assessed by immunoblotting. The relation of mitochondrial mRNA translation to muscle oxidative phenotype was assessed using PGC-1α transgenic overexpression (MCK-PGC-1α vs. wild-type mice) and comparing across muscle groups in wild-type mice. mtIF3 and TACO1 proteins were ~45% greater in VWR than sedentary (SED), and TACO1 and mtIF2 proteins were ~60% and 125% greater in WD than normal chow (NC). TUFM protein was ~50% lower in WD-SED than NC-SED, but ~50% greater in WD-VWR compared to NC-SED. CytB and ND4 were ~40% greater in VWR and ND4 was twofold greater with WD. TUFM, TACO1, ND4 and CytB were greater in MCK-PGC-1α compared to wild-type, and mtIF2/3 contents were not different. In oxidative muscle (soleus), mitochondrial translation machinery was elevated compared to mixed (gastrocnemius) or glycolytic (extensor digitorum longus) muscles. These data suggest a novel mechanism promoting mitochondrial function by translation of mitochondrial protein following PA. This may act to promote muscle health by PA in obesity.

Lee DE ，Brown JL ，Rosa ME ，Brown LA ，Perry RA ，Washington TA ，Greene NP ... -  《-》

Autophagy activation, not peroxisome proliferator-activated receptor γ coactivator 1α, may mediate exercise-induced improvements in glucose handling during diet-induced obesity.

What is the central question of this study? What are the individual and combined effects of muscle-specific peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) overexpression and physical activity during high-fat feeding on glucose and exercise tolerance? What is the main finding and its importance? Our main finding is that muscle-specific PGC-1α overexpression provides no protection against lipid-overload pathologies nor does it enhance exercise adaptations. Instead, physical activity, regardless of PGC-1α content, protects against high-fat diet-induced detriments. Activation of muscle autophagy was correlated with exercise protection, suggesting that autophagy might be a mediating factor for exercise-induced protection from lipid overload. The prevalence of glucose intolerance is alarmingly high. Efforts to promote mitochondrial biogenesis through peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) to mitigate glucose intolerance have been controversial. However, physical activity remains a primary means to alleviate the condition. The aim of this study was to determine the combined effects of muscle-specific overexpression of PGC-1α and physical activity on glucose handling during diet-induced obesity. Wild-type (WT, ∼20) and PGC-1α muscle transgenic (MCK-PGC-1α, ∼20) mice were given a Western diet (WD) at 8 weeks age and allowed to consume food ab libitum throughout the study. At 12 weeks of age, all animals were divided into sedentary (SED) or voluntary wheel running (VWR) interventions. At 7, 11 and 15 weeks of age, animals underwent glucose tolerance tests (GTT) and graded exercise tests (GXT). At 16 weeks of age, tissues were collected. At 11 weeks, the MCK-PGC-1α animals had 50% greater glucose tolerance integrated area under the curve compared with WT. However, at 15 weeks, SED animals also had greater GTT integrated area under the curve compared with VWR, regardless of genotype; furthermore, SED animals demonstrated reduced exercise capacity compared with earlier time points, which was not seen in VWR animals. Voluntary distance run per day was correlated with GTT in VWR-WT, but not VWR-MCK-PGC-1α mice. Voluntary wheel running and genotype independently resulted in a greater LC3II/LC3I ratio, suggesting enhanced autophagosome formation, which was correlated with exercise-induced improvements in GTT. In conclusion, artificially increasing mitochondrial content does not protect from lipid-induced pathologies nor does it augment exercise adaptations. Physical activity ameliorates the effects of lipid overload-induced glucose intolerance, an effect that appears to be related to enhanced activation of autophagy.

Rosa-Caldwell ME ，Brown JL ，Lee DE ，Blackwell TA ，Turner KW ，Brown LA ，Perry RA ，Haynie WS ，Washington TA ，Greene NP ... -  《-》

Moderate physical activity promotes basal hepatic autophagy in diet-induced obese mice.

Rosa-Caldwell ME ，Lee DE ，Brown JL ，Brown LA ，Perry RA Jr ，Greene ES ，Carvallo Chaigneau FR ，Washington TA ，Greene NP ... -  《-》