Endothelial HSP72 is not reduced in type 2 diabetes nor is it a key determinant of endothelial insulin sensitivity.

Impaired endothelial insulin signaling and consequent blunting of insulin-induced vasodilation is a feature of type 2 diabetes (T2D) that contributes to vascular disease and glycemic dysregulation. However, the molecular mechanisms underlying endothelial insulin resistance remain poorly known. Herein, we tested the hypothesis that endothelial insulin resistance in T2D is attributed to reduced expression of heat shock protein 72 (HSP72). HSP72 is a cytoprotective chaperone protein that can be upregulated with heating and is reported to promote insulin sensitivity in metabolically active tissues, in part via inhibition of JNK activity. Accordingly, we further hypothesized that, in individuals with T2D, 7 days of passive heat treatment via hot water immersion to waist level would improve leg blood flow responses to an oral glucose load (i.e., endogenous insulin stimulation) via induction of endothelial HSP72. In contrast, we found that: 1) endothelial insulin resistance in T2D mice and humans was not associated with reduced HSP72 in aortas and venous endothelial cells, respectively; 2) after passive heat treatment, improved leg blood flow responses to an oral glucose load did not parallel with increased endothelial HSP72; and 3) downregulation of HSP72 (via small-interfering RNA) or upregulation of HSP72 (via heating) in cultured endothelial cells did not impair or enhance insulin signaling, respectively, nor was JNK activity altered. Collectively, these findings do not support the hypothesis that reduced HSP72 is a key driver of endothelial insulin resistance in T2D but provide novel evidence that lower-body heating may be an effective strategy for improving leg blood flow responses to glucose ingestion-induced hyperinsulinemia.

Cardiac and respiratory muscle responses to dietary N-acetylcysteine in rats consuming a high-saturated fat, high-sucrose diet.

NEW FINDINGS: What is the central question of this study? This study addresses whether a high-fat, high-sucrose diet causes cardiac and diaphragm muscle abnormalities in male rats and whether supplementation with the antioxidant N-acetylcysteine reverses diet-induced dysfunction. What is the main finding and its importance? N-Acetylcysteine attenuated the effects of high-fat, high-sucrose diet on markers of cardiac hypertrophy and diastolic dysfunction, but neither high-fat, high-sucrose diet nor N-acetylcysteine affected the diaphragm. These results support the use of N-acetylcysteine to attenuate cardiovascular dysfunction induced by a 'Western' diet. ABSTRACT: Individuals with overweight or obesity display respiratory and cardiovascular dysfunction, and oxidative stress is a causative factor in the general aetiology of obesity and of skeletal and cardiac muscle pathology. Thus, this preclinical study aimed to define diaphragmatic and cardiac morphological and functional alterations in response to an obesogenic diet in rats and the therapeutic potential of an antioxidant supplement, N-acetylcysteine (NAC). Young male Wistar rats consumed ad libitum a 'lean' or high-saturated fat, high-sucrose (HFHS) diet for ∼22 weeks and were randomized to control or NAC (2 mg/ml in the drinking water) for the last 8 weeks of the dietary intervention. We then evaluated diaphragmatic and cardiac morphology and function. Neither HFHS diet nor NAC supplementation affected diaphragm-specific force, peak power or morphology. Right ventricular weight normalized to estimated body surface area, left ventricular fractional shortening and posterior wall maximal shortening velocity were higher in HFHS compared with lean control animals and not restored by NAC. In HFHS rats, the elevated deceleration rate of early transmitral diastolic velocity was prevented by NAC. Our data showed that the HFHS diet did not compromise diaphragmatic muscle morphology or in vitro function, suggesting other possible contributors to breathing abnormalities in obesity (e.g., abnormalities of neuromuscular transmission). However, the HFHS diet resulted in cardiac functional and morphological changes suggestive of hypercontractility and diastolic dysfunction. Supplementation with NAC did not affect diaphragm morphology or function but attenuated some of the cardiac abnormalities in the rats receiving the HFHS diet.

Protection against Doxorubicin-Induced Cardiac Dysfunction Is Not Maintained Following Prolonged Autophagy Inhibition.

Doxorubicin (DOX) is a highly effective chemotherapeutic agent used in the treatment of various cancer types. Nevertheless, it is well known that DOX promotes the development of severe cardiovascular complications. Therefore, investigation into the underlying mechanisms that drive DOX-induced cardiotoxicity is necessary to develop therapeutic countermeasures. In this regard, autophagy is a complex catabolic process that is increased in the heart following DOX exposure. However, conflicting evidence exists regarding the role of autophagy dysregulation in the etiology of DOX-induced cardiac dysfunction. This study aimed to clarify the contribution of autophagy to DOX-induced cardiotoxicity by specifically inhibiting autophagosome formation using a dominant negative autophagy gene 5 (ATG5) adeno-associated virus construct (rAAV-dnATG5). Acute (2-day) and delayed (9-day) effects of DOX (20 mg/kg intraperitoneal injection (i.p.)) on the hearts of female Sprague-Dawley rats were assessed. Our data confirm established detrimental effects of DOX on left ventricular function, redox balance and mitochondrial function. Interestingly, targeted inhibition of autophagy in the heart via rAAV-dnATG5 in DOX-treated rats ameliorated the increase in mitochondrial reactive oxygen species emission and the attenuation of cardiac and mitochondrial function, but only at the acute timepoint. Deviation in the effects of autophagy inhibition at the 2- and 9-day timepoints appeared related to differences in ATG5-ATG12 conjugation, as this marker of autophagosome formation was significantly elevated 2 days following DOX exposure but returned to baseline at day 9. DOX exposure may transiently upregulate autophagy signaling in the rat heart; thus, long-term inhibition of autophagy may result in pathological consequences.

Small-hairpin RNA and pharmacological targeting of neutral sphingomyelinase prevent diaphragm weakness in rats with heart failure and reduced ejection fraction.

Heart failure with reduced ejection fraction (HFREF) increases neutral sphingomyelinase (NSMase) activity and mitochondrial reactive oxygen species (ROS) emission and causes diaphragm weakness. We tested whether a systemic pharmacological NSMase inhibitor or short-hairpin RNA (shRNA) targeting NSMase isoform 3 (NSMase3) would prevent diaphragm abnormalities induced by HFREF caused by myocardial infarction. In the pharmacological intervention, we used intraperitoneal injection of GW4869 or vehicle. In the genetic intervention, we injected adeno-associated virus serotype 9 (AAV9) containing shRNA targeting NSMase3 or a scrambled sequence directly into the diaphragm. We also studied acid sphingomyelinase-knockout mice. GW4869 prevented the increase in diaphragm ceramide content, weakness, and tachypnea caused by HFREF. For example, maximal specific forces (in N/cm2) were vehicle [sham 31 ± 2 and HFREF 26 ± 2 ( P < 0.05)] and GW4869 (sham 31 ± 2 and HFREF 31 ± 1). Respiratory rates were (in breaths/min) vehicle [sham 61 ± 3 and HFREF 84 ± 11 ( P < 0.05)] and GW4869 (sham 66 ± 2 and HFREF 72 ± 2). AAV9-NSMase3 shRNA prevented heightening of diaphragm mitochondrial ROS and weakness [in N/cm2, AAV9-scrambled shRNA: sham 31 ± 2 and HFREF 27 ± 2 ( P < 0.05); AAV9-NSMase3 shRNA: sham 30 ± 1 and HFREF 30 ± 1] but displayed tachypnea. Both wild-type and ASMase-knockout mice with HFREF displayed diaphragm weakness. Our study suggests that activation of NSMase3 causes diaphragm weakness in HFREF, presumably through accumulation of ceramide and elevation in mitochondrial ROS. Our data also reveal a novel inhibitory effect of GW4869 on tachypnea in HFREF likely mediated by changes in neural control of breathing.

Daily muscle stretching enhances blood flow, endothelial function, capillarity, vascular volume and connectivity in aged skeletal muscle.

KEY POINTS: In aged rats, daily muscle stretching increases blood flow to skeletal muscle during exercise. Daily muscle stretching enhanced endothelium-dependent vasodilatation of skeletal muscle resistance arterioles of aged rats. Angiogenic markers and capillarity increased in response to daily stretching in muscles of aged rats. Muscle stretching performed with a splint could provide a feasible means of improving muscle blood flow and function in elderly patients who cannot perform regular aerobic exercise. ABSTRACT: Mechanical stretch stimuli alter the morphology and function of cultured endothelial cells; however, little is known about the effects of daily muscle stretching on adaptations of endothelial function and muscle blood flow. The present study aimed to determine the effects of daily muscle stretching on endothelium-dependent vasodilatation and muscle blood flow in aged rats. The lower hindlimb muscles of aged Fischer rats were passively stretched by placing an ankle dorsiflexion splint for 30 min day-1 , 5 days week-1 , for 4 weeks. Blood flow to the stretched limb and the non-stretched contralateral limb was determined at rest and during treadmill exercise. Endothelium-dependent/independent vasodilatation was evaluated in soleus muscle arterioles. Levels of hypoxia-induced factor-1α, vascular endothelial growth factor A and neuronal nitric oxide synthase were determined in soleus muscle fibres. Levels of endothelial nitric oxide synthase and superoxide dismutase were determined in soleus muscle arterioles, and microvascular volume and capillarity were evaluated by microcomputed tomography and lectin staining, respectively. During exercise, blood flow to plantar flexor muscles was significantly higher in the stretched limb. Endothelium-dependent vasodilatation was enhanced in arterioles from the soleus muscle from the stretched limb. Microvascular volume, number of capillaries per muscle fibre, and levels of hypoxia-induced factor-1α, vascular endothelial growth factor and endothelial nitric oxide synthase were significantly higher in the stretched limb. These results indicate that daily passive stretching of muscle enhances endothelium-dependent vasodilatation and induces angiogenesis. These microvascular adaptations may contribute to increased muscle blood flow during exercise in muscles that have undergone daily passive stretch.

Increased mitochondrial emission of reactive oxygen species and calpain activation are required for doxorubicin-induced cardiac and skeletal muscle myopathy.

Although doxorubicin (DOX) is a highly effective anti-tumour agent used to treat a variety of cancers, DOX administration is associated with significant side effects, including myopathy of both cardiac and skeletal muscles. The mechanisms responsible for DOX-mediated myopathy remain a topic of debate. We tested the hypothesis that both increased mitochondrial reactive oxygen species (ROS) emission and activation of the cysteine protease calpain are required for DOX-induced myopathy in rat cardiac and skeletal muscle. Cause and effect was determined by administering a novel mitochondrial-targeted anti-oxidant to prevent DOX-induced increases in mitochondrial ROS emission, whereas a highly-selective pharmacological inhibitor was exploited to inhibit calpain activity. Our findings reveal that mitochondria are a major site of DOX-mediated ROS production in both cardiac and skeletal muscle fibres and the prevention of DOX-induced increases in mitochondrial ROS emission protects against fibre atrophy and contractile dysfunction in both cardiac and skeletal muscles. Furthermore, our results indicate that DOX-induced increases in mitochondrial ROS emission are required to activate calpain in heart and skeletal muscles and, importantly, calpain activation is a major contributor to DOX-induced myopathy. Taken together, these findings show that increased mitochondrial ROS production and calpain activation are significant contributors to the development of DOX-induced myopathy in both cardiac and skeletal muscle fibres.

Mineralocorticoid receptors modulate vascular endothelial function in human obesity.

Obesity increases linearly with age and is associated with impaired vascular endothelial function and increased risk of cardiovascular disease. MRs (mineralocorticoid receptors) contribute to impaired vascular endothelial function in cardiovascular disease; however, their role in uncomplicated human obesity is unknown. Because plasma aldosterone levels are elevated in obesity and adipocytes may be a source of aldosterone, we hypothesized that MRs modulate vascular endothelial function in older adults in an adiposity-dependent manner. To test this hypothesis, we administered MR blockade (eplerenone; 100 mg/day) for 1 month in a balanced randomized double-blind placebo-controlled cross-over study to 22 older adults (ten men, 55-79 years) varying widely in adiposity [BMI (body mass index): 20-45 kg/m²], but who were free from overt cardiovascular disease. We evaluated vascular endothelial function [brachial artery FMD (flow-mediated dilation)] via ultrasonography) and oxidative stress (plasma F2-isoprostanes and vascular endothelial cell protein expression of nitrotyrosine and NADPH oxidase p47phox) during placebo and MR blockade. In the whole group, oxidative stress (P>0.05) and FMD did not change with MR blockade (6.39 ± 0.67 compared with 6.23 ± 0.73%; P=0.7). However, individual improvements in FMD in response to eplerenone were associated with higher total body fat (BMI: r=0.45, P=0.02; and dual-energy X-ray absorptiometry-derived percentage body fat: r=0.50, P=0.009) and abdominal fat (total: r=0.61, P=0.005; visceral: r=0.67, P=0.002; and subcutaneous: r=0.48, P=0.03). In addition, greater improvements in FMD with eplerenone were related to higher baseline fasting glucose (r=0.53, P=0.01). MRs influence vascular endothelial function in an adiposity-dependent manner in healthy older adults.

Targeting neuroendocrine abnormalities in Parkinson's disease with exercise.

Parkinson's Disease (PD) is a prevalent and complex age-related neurodegenerative condition for which there are no disease-modifying treatments currently available. The pathophysiological process underlying PD remains incompletely understood but increasing evidence points to multiple system dysfunction. Interestingly, the past decade has produced evidence that exercise not only reduces signs and symptoms of PD but is also potentially neuroprotective. Characterizing the mechanistic pathways that are triggered by exercise and lead to positive outcomes will improve understanding of how to counter disease progression and symptomatology. In this review, we highlight how exercise regulates the neuroendocrine system, whose primary role is to respond to stress, maintain homeostasis and improve resilience to aging. We focus on a group of hormones - cortisol, melatonin, insulin, klotho, and vitamin D - that have been shown to associate with various non-motor symptoms of PD, such as mood, cognition, and sleep/circadian rhythm disorder. These hormones may represent important biomarkers to track in clinical trials evaluating effects of exercise in PD with the aim of providing evidence that patients can exert some behavioral-induced control over their disease.

Behavior change techniques in digital physical activity interventions for breast cancer survivors: a systematic review.

Given the broad benefits of physical activity (PA) but low PA levels among breast cancer survivors (i.e., women who have received a breast cancer diagnosis), innovative and evidence-based techniques are needed to motivate and support exercise. This study systematically reviews the use of behavior change techniques (BCTs) in digital PA interventions for breast cancer survivors. Studies were retrieved from five electronic databases and were included if they (i) sampled exclusively female breast cancer survivors aged >18 years, (ii) involved a digital intervention with the primary purpose of increasing PA, (iii) included a BCT component, (iv) used a randomized or quasi-randomized design, and (v) were published from January 2000 to May 2022. Two coders independently extracted data. Twenty primary studies met the inclusion criteria and were included in this review. All interventions used at least one BCT (mean 4 ± 1, range 2-13); self-monitoring (85%) and goal setting (79%) were the most common BCTs. Twelve of 20 (60%) studies reported improvements in PA behavior in the intervention vs. control group, and self-monitoring and goal setting were the most commonly used BCTs in these studies. Of the 93 total BCTs, 66 were not used in any interventions in the review, including critical constructs for PA behavior change (e.g., biofeedback). BCTs, important facilitators of PA behavior change, are being underutilized in digital PA interventions for breast cancer survivors. Future research should incorporate more diverse BCTs to explore if they can add to the effectiveness of digital interventions for this population.

Physical activity (PA) has many benefits, yet PA levels are low among breast cancer survivors (i.e., women who have received a breast cancer diagnosis). This study reviews the use of behavior change techniques (BCTs) in digital PA interventions for breast cancer survivors. BCTs are evidence-based and are important for encouraging changes in health behaviors, such as PA. Twenty studies were included in this review. All interventions used at least one BCT (mean 4 ± 1, range 2­13); self-monitoring (85%) and goal setting (79%) were the most common BCTs. Twelve of 20 (60%) studies reported improvements in PA, and self-monitoring and goal setting were the most commonly used BCTs in these studies. Of the 93 total BCTs, 66 were not used in any interventions in the review. This finding reveals that many BCTs, which are important influencers of behavior change, are often not being used in digital PA interventions for breast cancer survivors. BCTs such as biofeedback (e.g., providing information on heart rate during exercise) and practical social support (e.g., virtual exercise coaching), could be helpful. Future research should include more diverse BCTs to explore if they can add to the usefulness of digital interventions for this population.

Low muscle mass is associated with a higher risk of all-cause and cardiovascular disease-specific mortality in cancer survivors.

OBJECTIVES: Individuals with prior cancer diagnosis are more likely to have low muscle mass (LMM) than their cancer-free counterparts. Understanding the effects of LMM on the prognosis of cancer survivors can be clinically important. The aim of this study was to investigate whether risks for all-cause and cardiovascular disease (CVD)-specific mortality differ by status of LMM in cancer survivors and a matched cohort without cancer history. METHODS: We used cohort data from the 1999-2006 and 2011-2014 National Health and Nutrition Examination Survey. Participants included 946 adults surviving for ≥1 since cancer diagnosis and a matched cohort (by age, sex, and race) without cancer history (N = 1857). LMM was defined by appendicular lean mass and body height (men <7.26 kg/m2, women <5.45 kg/m2). Death was ascertained via the National Death Index and cause of death was assessed via International Classification of Diseases, Tenth Revision. Multivariable Cox proportional hazards models were used to estimate adjusted hazard ratio (aHR) and 95% confidence interval (CI) of LMM. RESULTS: The mean age of cancer survivors and matched cohort was 60.6 y (SD 15) and 60.2 y (SD 14.9), respectively. The median follow-up was 10.5 y for survivors and 10.9 y for matched cohort. Overall, 22.2% of cancer survivors and 19.7% of the matched cohort had LMM, respectively. In all, 321 survivors (33.9%) and 495 participants (26.7%) in the matched cohort died during follow-up. CVD-specific deaths were identified in 58 survivors (6.1%) and 122 participants in the matched cohort (6.6%). The multivariable Cox model suggested that LMM was positively associated with all-cause (aHR, 1.73; 95% CI, 1.31-2.29) and CVD-specific (aHR, 2.13; 95% CI, 1.14-4.00) mortality in cancer survivors. The associations between LMM and risk for all-cause (aHR, 1.24; 95% CI, 0.98-1.56) and CVD-specific (aHR, 1.21; 95% CI, 0.75-1.93) mortality were not statistically significant in the matched cohort. CONCLUSION: Cancer survivors with LMM have an increased risk for all-cause and CVD-specific mortality. This increase appears to be larger than that in counterparts without cancer history.

Vascular smooth muscle responsiveness to nitric oxide is reduced in healthy adults with increased adiposity.

Vascular smooth muscle responsiveness to nitric oxide, as assessed by nitroglycerin-induced dilation (NID), is impaired in clinical cardiovascular disease, but its relation to adiposity is unknown. We determined the relation of NID to total and abdominal adiposity in healthy adults varying widely in adiposity. In 224 men and women [age, 18-79 years; body mass index (BMI), 16.4-42.2 kg/m(2)], we measured NID (brachial artery dilation to 0.4 mg sublingual nitroglycerin), total body adiposity [BMI and percent body fat (percent BF via dual-energy X-ray absorptiometry)], and indexes of abdominal adiposity [waist circumference (WC) and waist-to-hip ratio (WHR)]. In a subgroup (n = 74), we also measured total abdominal fat (TAF), abdominal visceral fat (AVF), and subcutaneous fat (ASF) using computed tomography. Based on multiple linear regression, NID was negatively related to BMI [part correlation coefficient (r(part)) = -0.19, P = 0.004] and abdominal adiposity (WC, r(part) = -0.22; WHR, r(part) = -0.19; TAF, r(part) = -0.36; AVF, r(part) = -0.36; and ASF, r(part) = -0.30; all P ≤ 0.009) independent of sex, but only tended to be related to total percent BF (r(part) = -0.12, P = 0.07). In a subgroup of subjects with the highest compared with the lowest amount of AVF, NID was 35% lower (P = 0.003). Accounting for systolic blood pressure, HDL cholesterol, glucose, insulin resistance, adiponectin, and brachial artery diameter reduced or abolished some of the relations between NID and adiposity. In conclusion, NID is or tends to be negatively associated with measures of total adiposity (BMI and percent BF, respectively) but is consistently and more strongly negatively associated with abdominal adiposity. Adiposity may influence NID in part via other cardiovascular risk factors.

Redox balance in the aging microcirculation: new friends, new foes, and new clinical directions.

Cardiovascular aging is associated with a decline in the function of the vascular endothelium. Considerable evidence indicates that age-induced impairment of endothelium-dependent vasodilation results from a reduction in the availability of nitric oxide (NO(•) ). NO(•) can be scavenged by reactive oxygen species (ROS), in particular by superoxide radical (O(2) (•-) ), and age-related increases in ROS have been demonstrated to contribute to reduced endothelium-dependent vasodilation in numerous large artery preparations. In contrast, emerging data suggest that ROS may play a compensatory role in endothelial function of the aging microvasculature. The primary goal of this review is to discuss reports in the literature which indicate that ROS function as important signaling molecules in the aging microvasculature. Emphasis is placed upon discussion of the emerging roles of hydrogen peroxide (H(2) O(2) ) and peroxynitrite (ONOO(•-) ) in the aging microcirculation. Overall, existing data in animal models suggest that maintenance in the balance of ROS is critical to successful microvascular aging. The limited work that has been performed to investigate the role of ROS in human microvascular aging is also discussed, and the need for future investigations of ROS signaling in older humans is considered.

Effects of sleep deprivation on endothelial function in adult humans: a systematic review.

Sleep deprivation is highly prevalent and is associated with increased cardiovascular disease (CVD) morbidity and mortality. Age-related alterations in sleep and chronobiology may exaggerate CVD susceptibility in older individuals. The mechanisms responsible for the association between sleep deprivation and CVD are not fully understood, but endothelial dysfunction may play a central role. Our objective was to conduct a systematic literature review to evaluate the evidence on the effects of sleep deprivation on endothelial function (EF). This review adhered to the PRISMA guidelines and was pre-registered with PROSPERO (#CRD42020192485, 07/24/2020). We searched PubMed, Web of Science, Embase, and Cochrane Library for articles published through May 1, 2020. Eligibility criteria included publication in English and use of well-established EF methodologies in adult humans. Two investigators independently performed the literature search, study selection, data extraction, risk-of-bias assessment, and qualitative data synthesis. Out of 3571 articles identified, 24 articles were included in the systematic review. Main findings include the following: (1) shorter sleep duration is associated with lower macrovascular EF; (2) not sleeping 7-9 h/night is linked with impaired microvascular EF; (3) sleep restriction impairs micro- and macrovascular EF; (4) acute total sleep deprivation impairs micro- and macrovascular EF but data on macrovascular EF are less consistent; and (5) shift work impairs macrovascular EF. In conclusion, sleep deprivation impairs EF, which may explain the link between insufficient sleep and CVD. Future investigations should fully elucidate the underlying mechanisms and develop strategies to combat the adverse endothelial effects of sleep deprivation across the lifespan.

Protein expression in vascular endothelial cells obtained from human peripheral arteries and veins.

Studying molecular mechanisms of vascular endothelial function in humans is difficult in part because of limited access to arteries. Access to peripheral veins is more practical. We determined if differences in protein expression of endothelial cells (EC) collected from a peripheral artery are reflected in measurements made on EC obtained from peripheral veins. EC were collected from the brachial artery and an antecubital vein of 106 healthy adults (60 men and 46 women, age 18-77 years). Quantitative immunofluorescence was used to measure protein expression of endothelial nitric oxide synthase (eNOS), Ser-1177 phosphorylated eNOS, manganese superoxide dismutase, nitrotyrosine, xanthine oxidase and nuclear factor-kappaB p65. Protein expression in EC obtained from brachial artery and antecubital vein sampling was moderately to strongly related (r = 0.59-0.81, all p < 0.0001, mean r = 0.70). Moreover, differences between subgroups in the lowest and highest tertiles of protein expression in EC obtained from arterial samples were consistently reflected in EC obtained from venous collections. These findings indicate that interindividual and group differences in expression of several proteins involved in nitric oxide production, oxidant production, antioxidant defense and inflammatory signaling in EC obtained from brachial artery sampling are consistently reflected in EC obtained from venous samples. Thus, EC collected from peripheral veins may provide a useful surrogate for EC obtained from arteries for measurements of EC protein expression in humans.

Aerobic Exercise Interventions for Patients in Opioid Maintenance Treatment: A Systematic Review.

BACKGROUND: Opioid maintenance treatment (OMT) is the standard for treatment of opioid use disorder, but some individuals on OMT experience disrupted sleep, heightened sensitivity to pain, and continued relapse to non-medical opioid use. An adjunctive treatment that has potential to address these shortcomings of OMT is aerobic exercise. OBJECTIVE: The aim of the present review was to identify and evaluate components of aerobic exercise interventions targeting OMT patients. METHODS: For this PROSPERO-registered review (ID CRD42020139626), studies were identified via electronic bibliographic databases, funded research (NIH RePORTER) and clinical trials databases (ClinicalTrials.gov), and reference sections of relevant manuscripts. Studies that evaluated the effects of an aerobic exercise intervention using a comparison condition or pretest-posttest design in adult OMT patients were included. RESULTS: Of 2971 unique records, three primary studies and one supplemental manuscript comprised the final sample. All studies were randomized trials involving supervised exercise interventions enrolling small samples of middle-aged OMT patients. Exercise interventions included a variety of aerobic and non-aerobic activities (e.g. flexibility exercises), and none controlled the dose of aerobic exercise. Few studies used objective measures of physical activity or cardiorespiratory fitness and there were no significant effects of adjunctive exercise on substance use outcomes, but tests of the latter were likely underpowered. CONCLUSIONS: Though early in the accumulation of evidence, interventions targeting aerobic exercise for OMT patients appear feasible, acceptable to patients, and beneficial. Longer-term studies that employ larger samples, include assessments of behavioral and biological mechanisms of change, more rigorous measurement of physical activity, and controlled doses of aerobic activity are warranted.

Pharmacological targeting of mitochondrial function and reactive oxygen species production prevents colon 26 cancer-induced cardiorespiratory muscle weakness.

Cancer cachexia is a syndrome characterized by profound cardiac and diaphragm muscle wasting, which increase the risk of morbidity in cancer patients due to failure of the cardiorespiratory system. In this regard, muscle relies greatly on mitochondria to meet energy requirements for contraction and mitochondrial dysfunction can result in muscle weakness and fatigue. In addition, mitochondria are a major source of reactive oxygen species (ROS) production, which can stimulate increased rates of muscle protein degradation. Therefore, it has been suggested that mitochondrial dysfunction may be an underlying factor that contributes to the pathology of cancer cachexia. To determine if pharmacologically targeting mitochondrial dysfunction via treatment with the mitochondria-targeting peptide SS-31 would prevent cardiorespiratory muscle dysfunction, colon 26 (C26) adenocarcinoma tumor-bearing mice were administered either saline or SS-31 daily (3 mg/kg/day) following inoculation. C26 mice treated with saline demonstrated greater ROS production and mitochondrial uncoupling compared to C26 mice receiving SS-31 in both the heart and diaphragm muscle. In addition, saline-treated C26 mice exhibited a decline in left ventricular function which was significantly rescued in C26 mice treated with SS-31. In the diaphragm, muscle fiber cross-sectional area of C26 mice treated with saline was significantly reduced and force production was impaired compared to C26, SS-31-treated animals. Finally, ventilatory deficits were also attenuated in C26 mice treated with SS-31, compared to saline treatment. These data demonstrate that C26 tumors promote severe cardiac and respiratory myopathy, and that prevention of mitochondrial dysfunction is sufficient to preclude cancer cachexia-induced cardiorespiratory dysfunction.

Effect of aerobic and resistance exercise training on inflammation, endothelial function and ambulatory blood pressure in middle-aged hypertensive patients.

OBJECTIVE: The current randomized controlled trial tested the hypothesis that both aerobic training and dynamic resistance training will improve inflammation, endothelial function and 24-h ambulatory blood pressure (ABP) in middle-aged adults with hypertension, but aerobic training would be more effective. METHODS: Forty-two hypertensive patients on at least one antihypertensive medication (19 men/23 women; 30-59 years of age) were randomly assigned to 12 weeks of supervised aerobic training (n = 15), resistance training (n = 15) or a nonexercise control (n = 12) group. Inflammation, endothelial function, 24-h ABP and related measures were evaluated at pre and postintervention. RESULTS: We found that aerobic training and resistance training were well tolerated. Both aerobic training and resistance training reduced daytime systolic ABP (-7.2 ±â€Š7.9 and -4.4 ±â€Š5.8 mmHg; P < 0.05) and 24-h systolic ABP (-5.6 ±â€Š6.2 and -3.2 ±â€Š6.4 mmHg; P < 0.05). aerobic training and resistance training both improved brachial artery flow-mediated dilation by 1.7 ±â€Š2.8 and 1.4 ±â€Š2.6%, respectively (7.59 ±â€Š3.36 vs. 9.26 ±â€Š2.93 and 7.24 ±â€Š3.18 vs. 8.58 ±â€Š2.37; pre vs. post P < 0.05). However, only aerobic training decreased markers of inflammation (C-reactive protein, monocyte chemoattractant protein-1, vascular cell adhesion molecule-1 and lectin-like oxidized LDL receptor-1) and endothelin-1 and increased nitrite and nitrate levels (P < 0.05). CONCLUSION: Healthcare providers should continue to emphasize aerobic training for hypertension management given the established role of nitric oxide, endothelin-1 and chronic low-level inflammation in the pathogenesis of cardiovascular disease. However, our study demonstrates that resistance training should also be encouraged for middle-aged hypertensive patients. Our results also suggest that even if patients are on antihypertensive medications, regular aerobic training and resistance training are beneficial for blood pressure control and cardiovascular disease risk reduction.

Nicotinamide riboside-A missing piece in the puzzle of exercise therapy for older adults?

Maintaining physical mobility is important for preventing age-related comorbidities in older adults. Endurance and resistance training prevent mobility loss in aging, but exercise alone does not always achieve the expected improvements in physical and cardiopulmonary function. Recent preclinical evidence suggests that a reason for the variability in exercise training responses may be the age-related dysregulation of the nicotinamide adenine dinucleotide (NAD+) metabolome. NAD+ is an essential enzymatic cofactor in energetic and signaling pathways. Endogenous NAD+ pool is lower in several chronic and degenerative diseases (e.g., cardiovascular diseases, Alzheimer's and Parkinson's diseases, muscular dystrophies), and also in aging. Exercise requires a higher energy expenditure than a resting state, thus a state of NAD+ insufficiency with reduced energy metabolism, could result in an inadequate exercise response. Recently, the NAD+ precursor nicotinamide riboside (NR), a vitamin B3 derivate, showed an ability to improve NAD+ metabolome homeostasis, restoring energy metabolism and cellular function in various organs in animals. NR has also been tested in older humans and is considered safe, but the effects of NR supplementation alone on physical performance are unclear. The purpose of this review is to examine the preclinical and clinical evidence on the effect of NR supplementation strategies alone and in combination with physical activity on mobility and skeletal muscle and cardiovascular function.

Impaired muscle mitochondrial energetics is associated with uremic metabolite accumulation in chronic kidney disease.

Chronic kidney disease (CKD) causes progressive skeletal myopathy involving atrophy, weakness, and fatigue. Mitochondria have been thought to contribute to skeletal myopathy; however, the molecular mechanisms underlying muscle metabolism changes in CKD are unknown. We employed a comprehensive mitochondrial phenotyping platform to elucidate the mechanisms of skeletal muscle mitochondrial impairment in mice with adenine-induced CKD. CKD mice displayed significant reductions in mitochondrial oxidative phosphorylation (OXPHOS), which was strongly correlated with glomerular filtration rate, suggesting a link between kidney function and muscle mitochondrial health. Biochemical assays uncovered that OXPHOS dysfunction was driven by reduced activity of matrix dehydrogenases. Untargeted metabolomics analyses in skeletal muscle revealed a distinct metabolite profile in CKD muscle including accumulation of uremic toxins that strongly associated with the degree of mitochondrial impairment. Additional muscle phenotyping found CKD mice experienced muscle atrophy and increased muscle protein degradation, but only male CKD mice had lower maximal contractile force. CKD mice had morphological changes indicative of destabilization in the neuromuscular junction. This study provides the first comprehensive evaluation of mitochondrial health in murine CKD muscle to our knowledge and uncovers several unknown uremic metabolites that strongly associate with the degree of mitochondrial impairment.

Mitochondrial accumulation of doxorubicin in cardiac and diaphragm muscle following exercise preconditioning.

Doxorubicin (DOX) is a highly effective anthracycline antibiotic. Unfortunately, the clinical use of DOX is limited by the risk of deleterious effects to cardiac and respiratory (i.e. diaphragm) muscle, resulting from mitochondrial reactive oxygen species (ROS) production. In this regard, exercise is demonstrated to protect against DOX-induced myotoxicity and prevent mitochondrial dysfunction. However, the protective mechanisms are currently unclear. We hypothesized that exercise may induce protection by increasing the expression of mitochondria-specific ATP-binding cassette (ABC) transporters and reducing mitochondrial DOX accumulation. Our results confirm this finding and demonstrate that two weeks of exercise preconditioning is sufficient to prevent cardiorespiratory dysfunction.