Exercise is a well-known non-pharmacological intervention to improve brain functions, including cognition, memory, and motor coordination. Contraction of skeletal muscles during exercise releases ...humoral factors that regulate the whole-body metabolism via interaction with other non-muscle organs. Myokines are muscle-derived effectors that regulate body metabolism by autocrine, paracrine, or endocrine action and were reportedly suggested as “exercise factors” that can improve the brain function. However, several aspects remain to be elucidated, namely the specific activities of myokines related to the whole-body metabolism or brain function, the mechanisms of regulation of other organs or cells, the sources of “exercise factors” that regulate brain function, and their mechanisms of interaction with non-muscle organs. In this paper, we present the physiological functions of myokines secreted by exercise, including regulation of the whole-body metabolism by interaction with other organs and adaptation of skeletal muscles to exercise. In addition, we discuss the functions of myokines that possibly contribute to exercise-induced improvement of brain function. Among several myokines, brain-derived neurotrophic factor (BDNF) is the most studied myokine that regulates adult neurogenesis and synaptic plasticity. However, the source of circulating BDNF and its upstream effector, insulin-like growth factor (IGF-1), and irisin and the effect size of peripheral BDNF, irisin, and IGF-1 released after exercise should be further investigated. Recently, cathepsin B has been reported to be secreted from skeletal muscles and upregulate BDNF following exercise, which was associated with improved cognitive function. We reviewed the level of evidence for the effect of myokine on the brain function. Level of evidence for the association of the change in circulating myokine following exercise and improvement of neuropsychiatric function is lower than the level of evidence for the benefit of exercise on the brain. Therefore, more clinical evidences for the association of myokine release after exercise and their effect on the brain function are required. Finally, we discuss the effect size of the action of myokines on cognitive benefits of exercise, in addition to other contributors, such as improvement of the cardiovascular system or the effect of “exercise factors” released from non-muscle organs, particularly in patients with sarcopenia.
Sarcopenia has been defined as a progressive decline of skeletal muscle mass, strength, and functions in elderly people. It is accompanied by physical frailty, functional disability, falls, ...hospitalization, and mortality, and is becoming a major geriatric disorder owing to the increasing life expectancy and growing older population worldwide. Experimental models are critical to understand the pathophysiology of sarcopenia and develop therapeutic strategies. Although its etiologies remain to be further elucidated, several mechanisms of sarcopenia have been identified, including cellular senescence, proteostasis imbalance, oxidative stress, and "inflammaging." In this article, we address three main aspects. First, we describe the fundamental aging mechanisms. Next, we discuss both in vitro and in vivo experimental models based on molecular mechanisms that have the potential to elucidate the biochemical processes integral to sarcopenia. The use of appropriate models to reflect sarcopenia and/or its underlying pathways will enable researchers to understand sarcopenia and develop novel therapeutic strategies for sarcopenia. Lastly, we discuss the possible molecular targets and the current status of drug candidates for sarcopenia treatment. In conclusion, the development of experimental models for sarcopenia is essential to discover molecular targets that are valuable as biochemical biomarkers and/or therapeutic targets for sarcopenia.
Aging impairs function in the nonischemic heart and is associated with mechanical remodeling. This process includes accumulation of collagen (i.e., fibrosis) and dysregulation of active matrix ...metalloproteinases (MMPs). Exercise training (ET) improves cardiac function, but the pathways of protection remain poorly understood. Young (3 mo) and old (31 mo) FBNF1 rats were assigned into sedentary and exercise groups, with ET group rats training on a treadmill 45 min/d, 5 d/wk for 12 wk. Nonlinear optical microscopy (NLOM), histology, immunohistochemistry (IHC), and Western blot analyses were performed on the left ventricle and septum. NLOM, IHC, and histological imaging revealed that ET reduced age‐associated elevation of collagen type I fibers. Active MMP‐1, active MMP‐2, and MMP‐14 in the ECM fraction of the left ventricle were reduced by aging, an effect abrogated by ET. Tissue inhibitor of MMP (TIMP‐1) was elevated with age but protected by ET. Transforming growth factor‐β (TGF‐β), upstream regulator of TIMP‐1, increased with age but was attenuated by ET. Therefore, exercise training could protect the aging heart against dysregulation of MMPs and fibrosis by suppressing elevation of TIMP‐1 and TGF‐β.—Kwak, H.‐B., Kim, J.‐H., Joshi, K., Yeh, A., Martinez, D. A., Lawler, J. M. Exercise training reduces fibrosis and matrix metalloproteinase dysregulation in the aging rat heart. FASEB J. 25, 1106–1117 (2011). www.fasebj.org
Although chemotherapy increases the survival rate of patients with various cancers, such treatment can induce acute or long-term cognitive dysfunction a phenomenon known as post-chemotherapy ...cognitive impairment (PCCI) or “chemobrain.” Exercise is known to positively affect brain function. Thus, the present study aimed to determine whether symptoms of chemobrain and disruptions in the neuroplasticity and functioning of hippocampal mitochondria can be prevented or relieved by exercise. Wistar rats were separated into the following groups: control, control plus exercise, chemobrain, and chemobrain plus exercise. For chemobrain induction, 2 mg/kg of doxorubicin (DOX) a widely utilized chemotherapeutic agent among patients with breast cancer was dissolved in saline and directly injected to the abdomen once every 4 weeks. The exercise groups were subjected to low-intensity treadmill, 6 days per week for 4 weeks. The Morris water maze and step-down avoidance tests were conducted to evaluate cognitive function, while neuroplasticity and mitochondrial function were assessed in the hippocampus and dentate gyrus. Decreased cognitive function were observed in the chemobrain group, along with decreases in levels of neurogenesis, brain derived neurotrophic factor (BDNF), tropomyosin-related kinase B (TrkB), Ca2+ retention in hippocampus. Rats of the chemobrain group also exhibited an increase in apoptosis, H2O2 emission and permeability transition pore by hippocampal mitochondria. However, exercise attenuated impairments in cognitive function, neuroplasticity, and mitochondrial function induced by DOX treatment. Therefore, the findings of the present study indicate that low-intensity exercise may assist in preventing cognitive dysfunction during or after chemotherapy in patients with various cancers, including breast cancer.
•Physical exercise attenuated impairments in cognitive function of chemobrain.•Physical exercise attenuated dysfunctions in hippocampal neuroplasticity of chemobrain.•Physical exercise attenuated dysfunctions in mitochondrial function of chemobrain.•Low-intensity exercise prevents cognitive dysfunction during or after chemotherapy.
Aging is characterized by a progressive impairment of (a) cardiac struc-ture including fibrosis and cardiomyocyte density, and (b) cardiac func-tion including stroke volume, ejection fraction, and ...cardiac output. The cardiac remodeling involves loss of cardiac myocytes, reactive hyper-trophy of the remaining cells, and increased extracellular matrix (ECM) and fibrosis in the aging heart, especially left ventricles. Fibrosis (i.e., accumulation of collagen) with aging is very critical in impairing cardiac function associated with increased myocardial stiffness. The balance of ECM remodeling via ECM synthesis and degradation is essential for normal cardiac structure and function. Thus an understanding of up-stream ECM regulatory factors such as matrix metalloproteinases (MMPs), tissue inhibitors of metalloproteinases (TIMPs), tumor necrosis factor-α (TNF-α), transforming growth factor-β (TGF-β), and myofibro-blasts is necessary for gaining new insights into managing cardiac re-modeling and dysfunction with aging. In contrast, exercise training ef-fectively improves cardiac function in both young and older individuals. Exercise training also improves maximal cardiovascular function by in -creasing stroke volume and cardiac output. However, limited data indi-cate that exercise training might attenuate collagen content and re-modeling in the aging heart. We recently found that 12 weeks of exer-cise training protected against geometric changes of collagen ECM in the aging heart and ameliorated age-associated dysregulation of ECM in the heart, as indicated by up-regulation of active MMPs as well as down-regulation of TIMPs and TGF-β. This review will provide a sum-mary and discussion of aging and exercise effects on fibrosis and up-stream regulators of ECM in the heart.
Although low socioeconomic status (SES) and decreased muscle strength have been found to be associated with the risk factors of non-alcoholic fatty liver disease (NAFLD), including insulin ...resistance, obesity, and metabolic syndrome, the associations among SES, muscle strength, and NAFLD are still unclear. We aimed to investigate the combined effect of SES and relative handgrip strength (HGS) on the risk of NAFLD in middle-aged adults. Data from 5272 middle-aged adults who participated in the Korea National Health and Nutrition Examination Surveys (KNHANES) from 2014-2018 were analyzed. NAFLD was defined using the hepatic steatosis index (HSI) > 36 and the comprehensive NAFLD score (CNS) ≥ 40 in the absence of other causes of liver disease. SES was based on a self-reported questionnaire. Overall, individuals with low SES (odds ratio (OR) = 1.703, 95% confidence interval (CI): 1.424-2.037,
< 0.001) or low HGS (OR = 12.161, 95% CI: 9.548-15.488,
< 0.001) had a significantly higher risk of NAFLD. The joint association analysis showed that a low SES combined with a low HGS (OR = 2.479, 95% CI: 1.351-4.549,
= 0.003) further significantly increased the risk of NAFLD when adjusted for all the covariates, compared with individuals with a high SES and a high HGS (OR = 1). The current findings suggest that both low SES and low HGS were independently and synergistically associated with an increased risk of NAFLD in middle-aged Korean adults.
Exposure to continuous light at night, including night-shift work or a nocturnal lifestyle, is emerging as a novel deleterious factor for weight gain and obesity. Here, we examined whether a single ...bout of bright light (BL) exposure at night affects energy metabolism via changes in circadian rhythm and nocturnal melatonin production. Ten healthy young men were randomized to a two-way crossover experimental design protocol: control (< 50 lux) and BL (approximately 10000 lux) conditions, with at least seven days of interval. The participants were exposed to each condition for 3 h (21:00-24:00) before sleep (0 lux, 00:00-07:00) in a room-type metabolic chamber. On each experimental night (21:00-07:00), energy expenditure, respiratory quotient (RQ), and substrate oxidation were measured to determine the energy metabolism. BL exposure prior to bedtime altered biological rhythms, disrupted the nocturnal decline in body temperature, and suppressed the melatonin level before sleeping, resulting in an increase in sleep latency. Indirect calorimetry data revealed that BL exposure significantly decreased the fat oxidation and increased the RQ, an indicator of the carbohydrate-to-fat oxidation ratio, throughout the whole period (light exposure and sleep). We revealed that acute BL exposure prior to bedtime exacerbated circadian rhythms and substrate oxidations, suggesting that chronic BL exposure at night may lead to obesity risk due to disturbances in circadian rhythms and macronutrient metabolism.
The heart is the primary pump that circulates blood through the entire cardiovascular system, serving many important functions in the body. Exercise training provides favorable anatomical and ...physiological changes that reduce the risk of heart disease and failure. Compared with pathological cardiac hypertrophy, exercise-induced physiological cardiac hypertrophy leads to an improvement in heart function. Exercise-induced cardiac remodeling is associated with gene regulatory mechanisms and cellular signaling pathways underlying cellular, molecular, and metabolic adaptations. Exercise training also promotes mitochondrial biogenesis and oxidative capacity leading to a decrease in cardiovascular disease. In this review, we summarized the exercise-induced adaptation in cardiac structure and function to understand cellular and molecular signaling pathways and mechanisms in preclinical and clinical trials.
Aging is associated with vulnerability to cardiovascular diseases, and mitochondrial dysfunction plays a critical role in cardiovascular disease pathogenesis. Exercise training is associated with ...benefits against chronic cardiac diseases. The purpose of this study was to determine the effects of aging and treadmill exercise training on mitochondrial function and apoptosis in the rat heart. Fischer 344 rats were divided into young sedentary (YS;
n
= 10, 4 months), young exercise (YE;
n
= 10, 4 months), old sedentary (OS;
n
= 10, 20 months), and old exercise (OE;
n
= 10, 20 months) groups. Exercise training groups ran on a treadmill at 15 m/min (young) or 10 m/min (old), 45 min/day, 5 days/week for 8 weeks. Morphological parameters, mitochondrial function, mitochondrial dynamics, mitophagy, and mitochondria-mediated apoptosis were analyzed in cardiac muscle. Mitochondrial O
2
respiratory capacity and Ca
2+
retention capacity gradually decreased, and mitochondrial H
2
O
2
emitting potential significantly increased with aging. Exercise training attenuated aging-induced mitochondrial H
2
O
2
emitting potential and mitochondrial O
2
respiratory capacity, while protecting Ca
2+
retention in the old groups. Aging triggered imbalanced mitochondrial dynamics and excess mitophagy, while exercise training ameliorated the aging-induced imbalance in mitochondrial dynamics and excess mitophagy. Aging induced increase in Bax and cleaved caspase-3 protein levels, while decreasing Bcl-2 levels. Exercise training protected against the elevation of apoptotic signaling markers by decreasing Bax and cleaved caspase-3 and increasing Bcl-2 protein levels, while decreasing the Bax/Bcl-2 ratio and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL)-positive myonuclei. These data demonstrate that regular exercise training prevents aging-induced impairment of mitochondrial function and mitochondria-mediated apoptosis in cardiac muscles.
Insulin resistance as a hallmark of type 2 DM (T2DM) plays a role in dementia by promoting pathological lesions or enhancing the vulnerability of the brain. Numerous studies related to ...insulin/insulin-like growth factor 1 (IGF-1) signaling are linked with various types of dementia. Brain insulin resistance in dementia is linked to disturbances in Aβ production and clearance, Tau hyperphosphorylation, microglial activation causing increased neuroinflammation, and the breakdown of tight junctions in the blood-brain barrier (BBB). These mechanisms have been studied primarily in Alzheimer's disease (AD), but research on other forms of dementia like vascular dementia (VaD), Lewy body dementia (LBD), and frontotemporal dementia (FTD) has also explored overlapping mechanisms. Researchers are currently trying to repurpose anti-diabetic drugs to treat dementia, which are dominated by insulin sensitizers and insulin substrates. Although it seems promising and feasible, none of the trials have succeeded in ameliorating cognitive decline in late-onset dementia. We highlight the possibility of repositioning anti-diabetic drugs as a strategy for dementia therapy by reflecting on current and previous clinical trials. We also describe the molecular perspectives of various types of dementia through the insulin/IGF-1 signaling pathway.
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