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1.
Exerc Sport Sci Rev ; 50(3): 162-170, 2022 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-35394967

RESUMO

This review proposes the novel hypothesis that heat can be used as an alternative therapy to exercise to improve hepatic mitochondrial function and glucose regulation in patients with nonalcoholic fatty liver disease. Although exercise has proven benefits in treating nonalcoholic fatty liver disease, barriers to exercise in the majority of patients necessitate an alternative method of treatment.


Assuntos
Hepatopatia Gordurosa não Alcoólica , Glicemia/metabolismo , Temperatura Alta , Humanos , Fígado/metabolismo , Mitocôndrias , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/terapia
2.
Int J Hyperthermia ; 38(1): 1650-1659, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34808071

RESUMO

AIMS: Type-2 diabetes mellitus (T2DM) is a common health condition which prevalence increases with age. Besides lifestyle modifications, passive heating could be a promising intervention to improve glycemic control. This study aimed to assess the efficacy of passive heat therapy on glycemic and cardiovascular parameters, and body weight among patients with T2DM. METHODS: A systematic review and meta-analysis were reported according to PRISMA Statement. We conducted a systematic search in three databases (MEDLINE, Embase, CENTRAL) from inception to 19 August 2021. We included interventional studies reporting on T2DM patients treated with heat therapy. The main outcomes were the changes in pre-and post-treatment cardiometabolic parameters (fasting plasma glucose, glycated plasma hemoglobin, and triglyceride). For these continuous variables, weighted mean differences (WMD) with 95% confidence intervals (CIs) were calculated. Study protocol number: CRD42020221500. RESULTS: Five studies were included in the qualitative and quantitative synthesis, respectively. The results showed a not significant difference in the hemoglobin A1c [WMD -0.549%, 95% CI (-1.262, 0.164), p = 0.131], fasting glucose [WMD -0.290 mmol/l, 95% CI (-0.903, 0.324), p = 0.355]. Triglyceride [WMD 0.035 mmol/l, 95% CI (-0.130, 0.200), p = 0.677] levels were comparable regarding the pre-, and post intervention values. CONCLUSION: Passive heating can be beneficial for patients with T2DM since the slight improvement in certain cardiometabolic parameters support that. However, further randomized controlled trials with longer intervention and follow-up periods are needed to confirm the beneficial effect of passive heat therapy.


Assuntos
Diabetes Mellitus Tipo 2 , Hipertermia Induzida , Glicemia , Diabetes Mellitus Tipo 2/terapia , Hemoglobinas Glicadas/análise , Temperatura Alta , Humanos
3.
J Cardiothorac Vasc Anesth ; 35(3): 780-785, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32571657

RESUMO

Heart disease is the leading cause of death in men and women in the United States. During the past several decades, research into the role of specific intracellular mediators, called exosomes, has advanced the understanding of molecular cardioprotection. Exosomes and the micro-RNAs within them may be potential targets for the development of genetically engineered or biosimilar medications for patients in heart failure or with ischemic cardiac disease. This review discusses anesthetic implications of exosome production and the future micro-RNA applications for cardioprotection.


Assuntos
Exossomos , Humanos , Masculino
4.
Am J Physiol Regul Integr Comp Physiol ; 315(4): R696-R707, 2018 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-29924632

RESUMO

Induction of the chaperone heat shock protein 72 (HSP72) through heat treatment (HT), exercise, or overexpression improves glucose tolerance and mitochondrial function in skeletal muscle. Less is known about HSP72 function in the liver where lipid accumulation can result in insulin resistance and nonalcoholic fatty liver disease (NAFLD). The purpose of this study was 1) to determine whether weekly in vivo HT induces hepatic HSP72 and improves glucose tolerance in rats fed a high-fat diet (HFD) and 2) to determine the ability of HSP72 to protect against lipid accumulation and mitochondrial dysfunction in primary hepatocytes. Male Wistar rats were fed an HFD for 15 wk and were given weekly HT (41°C, 20 min) or sham treatments (37°C, 20 min) for the final 7 wk. Glucose tolerance and insulin sensitivity were assessed, along with HSP72 induction and triglyceride storage, in the skeletal muscle and liver. The effect of an acute loss of HSP72 in primary hepatocytes was examined via siRNA. Weekly in vivo HT improved glucose tolerance, elevated muscle and hepatic HSP72 protein content, and reduced muscle triglyceride storage. In primary hepatocytes, mitochondrial morphology was changed, and fatty acid oxidation was reduced in small interfering HSP72 (siHSP72)-treated hepatocytes. Lipid accumulation following palmitate treatment was increased in siHSP72-treated hepatocytes. These data suggest that HT may improve systemic metabolism via induction of hepatic HSP72. Additionally, acute loss of HSP72 in primary hepatocytes impacts mitochondrial health as well as fat oxidation and storage. These findings suggest therapies targeting HSP72 in the liver may prevent NAFLD.


Assuntos
Proteínas de Choque Térmico HSP72/metabolismo , Hepatócitos/metabolismo , Hipertermia Induzida , Fígado/metabolismo , Hepatopatia Gordurosa não Alcoólica/terapia , Animais , Glicemia/metabolismo , Células Cultivadas , Dieta Hiperlipídica , Modelos Animais de Doenças , Ácidos Graxos/metabolismo , Proteínas de Choque Térmico HSP72/genética , Hepatócitos/ultraestrutura , Resistência à Insulina , Fígado/ultraestrutura , Masculino , Camundongos Endogâmicos C57BL , Mitocôndrias Hepáticas/metabolismo , Mitocôndrias Hepáticas/patologia , Músculo Esquelético/metabolismo , Hepatopatia Gordurosa não Alcoólica/etiologia , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/patologia , Oxirredução , Ratos Wistar , Transdução de Sinais , Regulação para Cima
5.
Muscle Nerve ; 51(4): 562-8, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24956997

RESUMO

INTRODUCTION: α7ß1 integrin links the extracellular matrix to the focal adhesion (FA) in skeletal muscle and serves as a stabilizing and signal relayer. Heat shock (HS) induces expression of proteins that interact with the FA. METHODS: Male Wistar rats were assigned to 1 of 3 groups: control (CON); eccentric exercise (EE); or EE+HS (HS). Soleus muscle was analyzed at 2 h and 48 h post-exercise. RESULTS: The 120-kDa α7 integrin decreased in the EE and HS groups, and the 70-kDa peptide decreased in the EE group at 2 h post-exercise. Total expression of focal adhesion kinase (FAK) and RhoA were decreased in EE and HS at 2 h post-exercise. Expression of phosphorylated FAK(397) decreased in the EE group but not the HS group at 2 h post-exercise. CONCLUSIONS: Long-duration EE may cause alterations in the FA in rat soleus muscle through the α7 integrin subunit and FAK.


Assuntos
Resposta ao Choque Térmico , Integrinas/metabolismo , Músculo Esquelético/metabolismo , Transdução de Sinais/fisiologia , Animais , Proteína-Tirosina Quinases de Adesão Focal/metabolismo , Temperatura Alta , Masculino , Modelos Animais , Movimento/fisiologia , Fosforilação , Condicionamento Físico Animal , Ratos Wistar
6.
Neurodegener Dis ; 13(1): 29-37, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24021858

RESUMO

BACKGROUND: Skeletal muscles play an important role in systemic glucose homeostasis and are purported to be the origin of the altered metabolic state observed in amyotrophic lateral sclerosis (ALS). OBJECTIVE: The purpose of this study was to evaluate whole-body and muscle-specific glucose metabolism in the SOD1-G93A mouse model of ALS. METHODS: We assessed glucose tolerance in early-, middle-, and late-stage SOD1-G93A and control mice using an intraperitoneal glucose tolerance test. We then measured the respiratory exchange ratio (CO2 production/O2 consumption) as a function of fasting and feeding using indirect calorimetry in a subset of male mice at these time points. Finally, muscles from all mice were harvested to evaluate basal and insulin-stimulated glucose transport in fast- and slow-twitch muscles. RESULTS: No changes in systemic glucose clearance were observed in SOD1-G93A mice at any stage, nor were there changes in fasting insulin levels. Indirect calorimetry revealed an increase in the respiratory exchange ratio during the fed state at middle, but not at early or late stages of disease. Middle-stage SOD1-G93A mice exhibited decreased insulin-stimulated glucose uptake in fast-twitch, but not slow-twitch, skeletal muscle. Late-stage SOD1-G93A mice exhibited decreased insulin-stimulated glucose uptake in both fast- and slow-twitch muscle, as well as increased basal (non-insulin-stimulated) glucose uptake. CONCLUSIONS: These results suggest that alterations in muscle metabolism occur in a fiber-type-specific manner in ALS, but do not necessarily lead to whole-body metabolic changes in SOD1-G93A mice.


Assuntos
Esclerose Lateral Amiotrófica/metabolismo , Glucose/metabolismo , Fibras Musculares Esqueléticas/metabolismo , Animais , Peso Corporal , Calorimetria Indireta , Modelos Animais de Doenças , Progressão da Doença , Jejum/metabolismo , Teste de Tolerância a Glucose , Insulina/sangue , Resistência à Insulina , Masculino , Camundongos , Camundongos Transgênicos , Superóxido Dismutase/genética
7.
J Alzheimers Dis ; 92(3): 1027-1035, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36847010

RESUMO

BACKGROUND: Individuals with mild cognitive impairment (MCI) have reduced lipid-stimulated mitochondrial respiration in skeletal muscle. A major risk factor for Alzheimer's disease (AD), the apolipoprotein E4 (APOE4) allele, is implicated in lipid metabolism and is associated with metabolic and oxidative stress that can result from dysfunctional mitochondria. Heat shock protein 72 (Hsp72) is protective against these stressors and is elevated in the AD brain. OBJECTIVE: Our goal was to characterize skeletal muscle ApoE and Hsp72 protein expression in APOE4 carriers in relationship to cognitive status, muscle mitochondrial respiration and AD biomarkers. METHODS: We analyzed previously collected skeletal muscle tissue from 24 APOE4 carriers (60y+) who were cognitively healthy (CH, n = 9) or MCI (n = 15). We measured ApoE and Hsp72 protein levels in muscle and phosphorylated tau181 (pTau181) levels in plasma, and leveraged previously collected data on APOE genotype, mitochondrial respiration during lipid oxidation, and VO2 max. RESULTS: Muscle ApoE (p = 0.013) and plasma pTau181 levels (p < 0.001) were higher in MCI APOE4 carriers. Muscle ApoE positively correlated with plasma pTau181 in all APOE4 carriers (R2 = 0.338, p = 0.003). Hsp72 expression negatively correlated with ADP (R2 = 0.775, p = <0.001) and succinate-stimulated respiration (R2 = 0.405, p = 0.003) in skeletal muscle of MCI APOE4 carriers. Plasma pTau181 negatively tracked with VO2 max in all APOE4 carriers (R2 = 0.389, p = 0.003). Analyses were controlled for age. CONCLUSION: This work supports a relationship between cellular stress in skeletal muscle and cognitive status in APOE4 carriers.


Assuntos
Doença de Alzheimer , Disfunção Cognitiva , Humanos , Idoso , Apolipoproteína E4/genética , Proteínas de Choque Térmico HSP72 , Apolipoproteínas E/genética , Doença de Alzheimer/genética , Disfunção Cognitiva/genética , Músculos , Biomarcadores , Apolipoproteína E3/genética
8.
bioRxiv ; 2023 May 29.
Artigo em Inglês | MEDLINE | ID: mdl-37398219

RESUMO

Exosomes are small extracellular vesicles (sEVs) of ~30-150 nm in diameter that have the same topology as the cell, are enriched in selected exosome cargo proteins, and play important roles in health and disease. To address large unanswered questions regarding exosome biology in vivo, we created the exomap1 transgenic mouse model. In response to Cre recombinase, exomap1 mice express HsCD81mNG, a fusion protein between human CD81, the most highly enriched exosome protein yet described, and the bright green fluorescent protein mNeonGreen. As expected, cell type-specific expression of Cre induced the cell type-specific expression of HsCD81mNG in diverse cell types, correctly localized HsCD81mNG to the plasma membrane, and selectively loaded HsCD81mNG into secreted vesicles that have the size (~80 nm), topology (outside out), and content (presence of mouse exosome markers) of exosomes. Furthermore, mouse cells expressing HsCD81mNG released HsCD81mNG-marked exosomes into blood and other biofluids. Using high-resolution, single-exosome analysis by quantitative single molecule localization microscopy, we show here that that hepatocytes contribute ~15% of the blood exosome population whereas neurons contribute <1% of blood exosomes. These estimates of cell type-specific contributions to blood EV population are consistent with the porosity of liver sinusoidal endothelial cells to particles of ~50-300 nm in diameter, as well as with the impermeability of blood-brain and blood-neuron barriers to particles >5 nm in size. Taken together, these results establish the exomap1 mouse as a useful tool for in vivo studies of exosome biology, and for mapping cell type-specific contributions to biofluid exosome populations. In addition, our data confirm that CD81 is a highly-specific marker for exosomes and is not enriched in the larger microvesicle class of EVs.

9.
Extracell Vesicle ; 22023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-39372847

RESUMO

Exosomes are small extracellular vesicles (sEVs) of ~30-150 nm in diameter that are enriched in exosome marker proteins and play important roles in health and disease. To address large unanswered questions regarding exosome biology in vivo, we created the Exomap1 transgenic mouse, which in response to Cre recombinase expresses the most highly enriched exosomal marker protein known, human CD81, fused to mNeonGreen (HsCD81mNG), and prior to Cre expresses a mitochondrial red fluorescent protein. Validation of the exomap1 mouse with eight distinct Cre drivers demonstrated that HsCD81mNG was expressed only in response to Cre, that murine cells correctly localized HsCD81mNG to the plasma membrane, and that this led to the secretion of HsCD81mNG in EVs that had the size (~70-80 nm), topology, and composition of exosomes. Furthermore, cell type-specific activation of the exomap1 transgene allowed us to use quantitative single molecule localization microscopy to calculate the cell type-specific contribution to biofluid exosome populations. Specifically, we show that neurons contribute ~1% to plasma and cerebrospinal fluid exosome populations whereas hepatocytes contribute ~15% to plasma exosome populations, numbers that reflect the known vascular permeabilities of brain and liver. These observations validate the use of Exomap1 mouse models for in vivo studies of exosome biology.

10.
J Vis Exp ; (179)2022 01 10.
Artigo em Inglês | MEDLINE | ID: mdl-35068480

RESUMO

Extracellular vesicles (EVs) are nanometer-sized vesicles with a lipid bilayer that are secreted by most cells. EVs carry a multitude of different biological molecules, including protein, lipid, DNA, and RNA, and are postulated to facilitate cell-to-cell communication in diverse tissues and organs. Recently, EVs have attracted significant attention as biomarkers for diagnostics and therapeutic agents for various diseases. Many methods have been developed for EV characterization. However, current methods for EV analysis all have different limitations. Thus, developing efficient and effective methods for EV isolation and characterization remains one of the crucial steps for this cutting-edge research field as it matures. Here, we provide a detailed protocol outlining a single-particle interferometric reflectance imaging sensor (SP-IRIS), as a method that is capable of detecting and characterizing EVs from unpurified biological sources and purified EVs by other methodologies. This advanced technique can be used for multi-level and comprehensive measurements for the analysis of EV size, EV count, EV phenotype, and biomarker colocalization.


Assuntos
Vesículas Extracelulares , Biomarcadores/metabolismo , Vesículas Extracelulares/metabolismo , Interferometria , Dinâmica Populacional , Proteínas/metabolismo
11.
Artigo em Inglês | MEDLINE | ID: mdl-36444378

RESUMO

Introduction: The symptoms of Amyotrophic Lateral Sclerosis (ALS) include muscle weakness and eventual paralysis. These symptoms result from denervation of the neuromuscular junction (NMJ) and motor neuron cell death in the brain and spinal cord. Due to the "dying back" pattern of motor neuron degeneration, protecting NMJs should be a therapeutic priority. Although exercise has the potential to protect against NMJ denervation, its use in ALS has been controversial. Most preclinical studies have focused on aerobic exercise, which report that exercise can be beneficial at moderate intensities. The effects of resistance exercise on NMJ preservation in limb muscles have not been explored. Methods: We trained male SOD1-G93A rats, which model ALS, to perform a unilateral isometric forelimb resistance exercise task. This task allows within-animal comparisons of trained and untrained forelimbs. We then determined the effects of isometric resistance exercise on NMJ denervation and AMP kinase (AMPK) activation in forelimb muscles. Results: Our results revealed that SOD1-G93A rats were able to learn and perform the task similarly to wildtype rats, even after loss of body weight. SOD1-G93A rats exhibited significantly greater NMJ innervation in their trained vs their untrained forelimb biceps muscles. Measures of activated (phosphorylated) AMPK (pAMPK) were also greater in the trained vs untrained forelimb triceps muscles. Discussion: These results demonstrate that isometric resistance exercise may protect against NMJ denervation in ALS. Future studies are required to determine the extent to which our findings generalize to female SOD1-G93A rats and to other subtypes of ALS.

12.
Brain Plast ; 8(2): 153-168, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36721393

RESUMO

An inaugural workshop supported by "The Leo and Anne Albert Charitable Trust," was held October 4-7, 2019 in Scottsdale, Arizona, to focus on the effects of exercise on the brain and to discuss how physical activity may prevent or delay the onset of aging-related neurodegenerative conditions. The Scientific Program Committee (led by Dr. Jeff Burns) assembled translational, clinical, and basic scientists who research various aspects of the effects of exercise on the body and brain, with the overall goal of gaining a better understanding as to how to delay or prevent neurodegenerative diseases. In particular, research topics included the links between cardiorespiratory fitness, the cerebrovasculature, energy metabolism, peripheral organs, and cognitive function, which are all highly relevant to understanding the effects of acute and chronic exercise on the brain. The Albert Trust workshop participants addressed these and related topics, as well as how other lifestyle interventions, such as diet, affect age-related cognitive decline associated with Alzheimer's and other neurodegenerative diseases. This report provides a synopsis of the presentations and discussions by the participants, and a delineation of the next steps towards advancing our understanding of the effects of exercise on the aging brain.

13.
J Physiol ; 589(Pt 8): 2041-54, 2011 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-21486807

RESUMO

Previous studies suggest oestrogen receptor α (ERα) is involved in oestrogen-mediated regulation of glucose metabolism and is critical for maintenance of whole body insulin action. Despite this, the effect of direct ERα modulation in insulin-responsive tissues is unknown. The purpose of the current study was to determine the impact of ERα activation, using the ER subtype-selective ligand propylpyrazoletriyl (PPT), on skeletal muscle glucose uptake. Two-month-old female Sprague-Dawley rats, ovariectomized for 1 week, were given subcutaneous injections of PPT (10 mg kg⁻¹), oestradiol benzoate (EB; 20 µg kg⁻¹), the ERß agonist diarylpropionitrile (DPN, 10 mg kg⁻¹) or vehicle every 24 h for 3 days. On the fourth day, insulin-stimulated skeletal muscle glucose uptake was measured in vitro and insulin signalling intermediates were assessed via Western blotting.Activation of ERα with PPT resulted in increased insulin-stimulated glucose uptake into the slow-twitch soleus and fast-twitch extensor digitorum longus (EDL)muscles, activation of insulin signalling intermediates (as measured by phospho-Akt (pAkt) and pAkt substrate (PAS)) and phosphorylation of AMP-activated protein kinase (AMPK). GLUT4 protein was increased only in the EDL muscle. Rats treated with EB or DPN for 3 days did not show an increase in insulin-stimulated skeletal muscle glucose uptake compared to vehicle-treated animals. These new findings reveal that direct activation of ERα positively mediates glucose uptake and insulin action in skeletal muscle. Evidence that oestrogens and ERα stimulate glucose uptake has important implications for understanding mechanisms of glucose homeostasis, particularly in postmenopausal women.


Assuntos
Receptor alfa de Estrogênio/agonistas , Glucose/metabolismo , Insulina/metabolismo , Músculo Esquelético/efeitos dos fármacos , Pirazóis/administração & dosagem , Proteínas Quinases Ativadas por AMP/metabolismo , Análise de Variância , Animais , Transporte Biológico , Western Blotting , Estradiol/administração & dosagem , Estradiol/análogos & derivados , Receptor alfa de Estrogênio/metabolismo , Receptor beta de Estrogênio/agonistas , Receptor beta de Estrogênio/metabolismo , Feminino , Proteínas Ativadoras de GTPase/metabolismo , Transportador de Glucose Tipo 4/metabolismo , Injeções Subcutâneas , Músculo Esquelético/metabolismo , Nitrilas/administração & dosagem , Ovariectomia , Fenóis , Fosforilação , Propionatos/administração & dosagem , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Fatores de Tempo
14.
Exerc Sport Sci Rev ; 39(1): 34-42, 2011 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-21088604

RESUMO

Endogenous heat shock proteins (HSP) are decreased in disease states associated with insulin resistance and aging. Induction of HSPs has been shown to decrease oxidative stress, inhibit inflammatory pathways, and enhance metabolic characteristics in skeletal muscle. As such, HSPs have the potential to function as an important defense system against the development of insulin resistance and type 2 diabetes.


Assuntos
Proteínas de Choque Térmico/metabolismo , Resistência à Insulina , Músculo Esquelético/metabolismo , Animais , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/prevenção & controle , Temperatura Alta , Humanos , Insulina/metabolismo , Estresse Oxidativo
15.
Function (Oxf) ; 2(2): zqab001, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33629069

RESUMO

Nonacholic fatty liver disease, or hepatic steatosis, is the most common liver disorder affecting the western world and currently has no pharmacologic cure. Thus, many investigations have focused on alternative strategies to treat or prevent hepatic steatosis. Our laboratory has shown that chronic heat treatment (HT) mitigates glucose intolerance, insulin resistance, and hepatic steatosis in rodent models of obesity. Here, we investigate the direct bioenergetic mechanism(s) surrounding the metabolic effects of HT on hepatic mitochondria. Utilizing mitochondrial proteomics and respiratory function assays, we show that one bout of acute HT (42°C for 20 min) in male C57Bl/6J mice (n = 6/group) triggers a hepatic mitochondrial heat shock response resulting in acute reductions in respiratory capacity, degradation of key mitochondrial enzymes, and induction of mitophagy via mitochondrial ubiquitination. We also show that chronic bouts of HT and recurrent activation of the heat shock response enhances mitochondrial quality and respiratory function via compensatory adaptations in mitochondrial organization, gene expression, and transport even during 4 weeks of high-fat feeding (n = 6/group). Finally, utilizing a liver-specific heat shock protein 72 (HSP72) knockout model, we are the first to show that HSP72, a protein putatively driving the HT metabolic response, does not play a significant role in the hepatic mitochondrial adaptation to acute or chronic HT. However, HSP72 is required for the reductions in blood glucose observed with chronic HT. Our data are the first to suggest that chronic HT (1) improves hepatic mitochondrial respiratory efficiency via mitochondrial remodeling and (2) reduces blood glucose in a hepatic HSP72-dependent manner.


Assuntos
Resistência à Insulina , Hepatopatia Gordurosa não Alcoólica , Camundongos , Animais , Masculino , Glicemia/metabolismo , Mitocôndrias , Hepatopatia Gordurosa não Alcoólica/metabolismo , Resistência à Insulina/genética
16.
J Alzheimers Dis Rep ; 5(1): 469-475, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34368631

RESUMO

BACKGROUND: Aerobic capacity is associated with metabolic, cardiovascular, and neurological health. Low-capacity runner (LCR) rats display low aerobic capacity, metabolic dysfuction, and spatial memory deficits. A heat treatment (HT) can improve metabolic dysfunction in LCR peripheral organs after high fat diet (HFD). Little is known about metabolic changes in the brains of these rats following HT. OBJECTIVE: Our objective was to examine the extent to which high or low aerobic capacity impacts Akt (a protein marker of metabolism) and heat shock protein 72 (HSP72, a marker of heat shock response) after HFD and HT in hippocampus. METHODS: We measured phosphorylated Akt (pAkt) in the striatum and hippocampus, and HSP72 in the hippocampus, of HFD-fed and chow-fed LCR and high-capacity runner (HCR) rats with and without HT. RESULTS: pAkt was lower in the hippocampus of chow-fed LCR than HCR rats. HFD resulted in greater pAkt in LCR but not HCR rats, but HT resulted in lower pAkt in the LCR HFD group. HSP72 was greater in both HCR and LCR rat hippocampus after HT. The HFD blunted this effect in LCR compared to HCR hippocampus. CONCLUSION: The abnormal phosphorylation of Akt and diminished HSP response in the hippocampus of young adult LCR rats might indicate early vulnerability to metabolic challenges in this key brain region associated with learning and memory.

17.
Am J Physiol Regul Integr Comp Physiol ; 299(4): R1082-90, 2010 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-20702796

RESUMO

Despite numerous clinical studies supporting a link between type 2 diabetes (T2D) and Parkinson's disease (PD), the clinical literature remains equivocal. We, therefore, sought to address the relationship between insulin resistance and nigrostriatal dopamine (DA) in a preclinical animal model. High-fat feeding in rodents is an established model of insulin resistance, characterized by increased adiposity, systemic oxidative stress, and hyperglycemia. We subjected rats to a normal chow or high-fat diet for 5 wk before infusing 6-hydroxydopamine (6-OHDA) into the medial forebrain bundle. Our goal was to determine whether a high-fat diet and the resulting peripheral insulin resistance would exacerbate 6-OHDA-induced nigrostriatal DA depletion. Prior to 6-OHDA infusion, animals on the high-fat diet exhibited greater body weight, increased adiposity, and impaired glucose tolerance. Two weeks after 6-OHDA, locomotor activity was tested, and brain and muscle tissue was harvested. Locomotor activity did not differ between the groups nor did cholesterol levels or measures of muscle atrophy. High-fat-fed animals exhibited higher homeostatic model assessment of insulin resistance (HOMA-IR) values and attenuated insulin-stimulated glucose uptake in fast-twitch muscle, indicating decreased insulin sensitivity. Animals in the high-fat group also exhibited greater DA depletion in the substantia nigra and the striatum, which correlated with HOMA-IR and adiposity. Decreased phosphorylation of HSP27 and degradation of IκBα in the substantia nigra indicate increased tissue oxidative stress. These findings support the hypothesis that a diet high in fat and the resulting insulin resistance may lower the threshold for developing PD, at least following DA-specific toxin exposure.


Assuntos
Gorduras na Dieta/toxicidade , Degeneração Neural/patologia , Doença de Parkinson Secundária/patologia , Animais , Glicemia/metabolismo , Peso Corporal/fisiologia , Colesterol/sangue , Cromatografia Líquida de Alta Pressão , Dopamina/fisiologia , Ingestão de Alimentos/fisiologia , Epididimo/metabolismo , Teste de Tolerância a Glucose , Peróxido de Hidrogênio , Insulina/sangue , Resistência à Insulina/fisiologia , Ferro/metabolismo , Masculino , Camundongos , Músculo Esquelético/metabolismo , Neostriado/fisiologia , Neurônios/fisiologia , Oxidopamina , Doença de Parkinson Secundária/induzido quimicamente , Ratos , Ratos Endogâmicos F344 , Substância Negra/fisiologia , Simpatolíticos
18.
J Appl Physiol (1985) ; 129(6): 1468-1476, 2020 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-32969779

RESUMO

Alzheimer's disease (AD) is the most common neurodegenerative disease, yet there are no disease-modifying treatments available and there is no cure. It is becoming apparent that metabolic and vascular conditions such as type 2 diabetes (T2D) and hypertension promote the development and accumulation of Alzheimer's disease-related dementia pathologies. To this end, aerobic exercise, which is a common lifestyle intervention for both metabolic disease and hypertension, is shown to improve brain health during both healthy aging and dementia. However, noncompliance or other barriers to exercise response are common in exercise treatment paradigms. In addition, reduced intracellular proteostasis and mitochondrial function could contribute to the etiology of AD. Specifically, compromised chaperone systems [i.e., heat shock protein (HSP) systems] can contribute to protein aggregates (i.e., ß-amyloid plaques and neurofibrillary tangles) and reduced mitochondrial quality control (i.e., mitophagy). Therefore, novel therapies that target whole body metabolism, the vasculature, and chaperone systems (like HSPs) are needed to effectively treat AD. This review focuses on the role of heat therapy in the treatment and prevention of AD. Heat therapy has been independently shown to reduce whole body insulin resistance, improve vascular function, activate interorgan cross talk via endocytic vesicles, and activate HSPs to improve mitochondrial function and proteostasis in a variety of tissues. Thus, heat therapy could offer immense clinical benefit to patients suffering from AD. Importantly, future studies in patients are needed to determine the safety and efficacy of heat therapy in preventing AD.


Assuntos
Doença de Alzheimer , Diabetes Mellitus Tipo 2 , Doenças Neurodegenerativas , Doença de Alzheimer/terapia , Encéfalo , Cognição , Humanos
19.
J Appl Physiol (1985) ; 106(4): 1425-34, 2009 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-19179648

RESUMO

The antioxidant alpha-lipoic acid (LA) has been shown to improve insulin action in high-fat (HF)-fed animal models, yet little is known about its underlying mechanisms of action. We hypothesize that LA acts by inducing heat shock proteins (HSPs), which then inhibit stress kinases known to interfere with insulin signaling intermediates. Male Wistar rats were fed a HF diet (60% calories from fat) for 6 wk, while controls received a chow diet (10% calories from fat). One-half of the rats in each group received daily LA injections (30 mg/kg body wt). In rats fed a HF diet, LA increased expression of HSP72 and activation of HSP25 in soleus muscle, but it had no effect on HSPs in muscle from chow-fed rats. LA treatment reduced phosphorylation of c-Jun NH(2)-terminal kinase (JNK) and inhibitor of kappaB kinase-beta (IKKbeta) activity (IkappaBalpha protein levels) in rats fed a HF diet and effectively restored insulin responsiveness, as seen by insulin-stimulated phosphorylated Akt/Akt and 2-deoxyglucose uptake in soleus muscle. LA also induced activation of p38 MAPK and AMP-activated protein kinase, proteins previously implicated in insulin-independent glucose uptake. In addition, acute LA treatment induced HSPs in vitro in L6 muscle cells and prevented the activation of JNK and IKKbeta with stimulants such as anisomycin and TNF-alpha, respectively. In conclusion, our results suggest chronic LA treatment results in stress kinase inhibition and improved insulin signaling through a HSP-mediated mechanism.


Assuntos
Antioxidantes/farmacologia , Gorduras na Dieta/farmacologia , Proteínas de Choque Térmico/biossíntese , Insulina/fisiologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Músculo Esquelético/fisiologia , Transdução de Sinais/efeitos dos fármacos , Ácido Tióctico/farmacologia , Quinases Proteína-Quinases Ativadas por AMP , Animais , Western Blotting , Peso Corporal/efeitos dos fármacos , Células Cultivadas , Inibidores Enzimáticos/farmacologia , Glucose/metabolismo , Quinase I-kappa B/biossíntese , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Masculino , Proteínas Quinases/metabolismo , Ratos , Ratos Wistar , Estimulação Química , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
20.
J Appl Physiol (1985) ; 105(3): 839-48, 2008 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-18599680

RESUMO

Aging is associated with an increase in insulin resistance in skeletal muscle, yet the underlying mechanism is not well established. We hypothesize that with aging, a chronic increase in stress kinase activation, coupled with a decrease in oxidative capacity, leads to insulin resistance in skeletal muscle. In aged (24 mo old) and young (3 mo old) Fischer 344 rats, 2-deoxyglucose uptake and insulin signaling [as measured by phosphorylation of insulin receptor substrate-1 (IRS-1), Akt (protein kinase B), and Akt substrate of 160 kDa (AS160)] decreased significantly with age. Activation of, c-Jun NH(2)-terminal kinase (JNK), glycogen serine kinase-3beta (GSK-3beta), and degradation of IkappaBalpha by the upstream inhibitor of kappa B kinase (IKKbeta), as measured by Western blot analysis, were increased with age in both soleus and epitrochlearis (Epi) muscles. However, much higher activation of these kinases in Epi muscles from young rats compared with soleus results in a greater effect of these kinases on insulin signaling in fast-twitch muscle with age. Heat shock protein (HSP) 72 expression and phosphorylation of HSP25 were higher in soleus compared with Epi muscles, and both parameters decreased with age. Age and fiber type differences in cytochrome oxidase activity are consistent with observed changes in HSP expression and activation. Our results demonstrate a significant difference in the ability of slow-twitch and fast-twitch muscles to respond to insulin and regulate glucose with age. A greater constitutive HSP expression and lower stress kinase activation may account for the ability of slow-twitch muscles to preserve the capacity to respond to insulin and maintain glucose homeostasis with age.


Assuntos
Envelhecimento/metabolismo , Proteínas de Choque Térmico/metabolismo , Insulina/metabolismo , Fibras Musculares de Contração Rápida/enzimologia , Fibras Musculares de Contração Lenta/enzimologia , Músculo Esquelético/enzimologia , Proteínas Quinases/metabolismo , Transdução de Sinais , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Fatores Etários , Animais , Desoxiglucose/metabolismo , Quinase 3 da Glicogênio Sintase/metabolismo , Glicogênio Sintase Quinase 3 beta , Proteínas de Choque Térmico HSP27 , Proteínas de Choque Térmico HSP72/metabolismo , Homeostase , Quinase I-kappa B/metabolismo , Proteínas I-kappa B/metabolismo , Proteínas Substratos do Receptor de Insulina , Resistência à Insulina , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Masculino , Inibidor de NF-kappaB alfa , Proteínas de Neoplasias/metabolismo , Fosforilação , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos , Ratos Endogâmicos F344
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