Role of metabolic stress for enhancing muscle adaptations: Practical applications

Metabolic stress is a physiological process that occurs during exercise in response to low energy that leads to metabolite accumulation [lactate, phosphate inorganic(Pi) and ions of hydrogen(H^+)] in muscle cells.Traditional exercise protocol(i.e., Resistance training) has an important impact on the increase of metabolite accumulation, which influences hormonal release, hypoxia, reactive oxygen species(ROS) production and cell swelling.Changes in acute exercise routines, such as intensity, volume and rest between sets, are determinants for the magnitude of metabolic stress, furthermore, different types of training, such as lowintensity resistance training plus blood flow restriction and high intensity interval training, could be used to maximize metabolic stress during exercise.Thus, the objective of this review is to describe practical applications that induce metabolic stress and the potential effects of metabolic stress to increase systemic hormonal release, hypoxia, ROS production, cell swelling and muscle adaptations.

AB015.Metabolic stress in glaucoma engages early activation of the energy biosensor adenosine monophosphate-activated protein kinase leading to neuronal dysfunction

Background:Metabolic stress has been proposed to contribute to neuronal damage in glaucoma,but the mechanism driving this response is not understood.The adenosine monophosphate-activated protein kinase(AMPK)is a master regulator of energy homeostasis that becomes active at the onset of energy stress.AMPK is a potent inhibitor of the mammalian target of rapamycin complex 1(mTORC1),which we showed is essential for the maintenance of retinal ganglion cell(RGC)dendrites,synapses,and survival.Here,we tested the hypothesis that AMPK is an early mediator of metabolic stress in glaucoma.Methods:Unilateral elevation of intraocular pressure was induced by injection of magnetic microbeads into the anterior chamber of mice expressing yellow fluorescent protein in RGCs.Inhibition of AMPK was achieved by administration of siRNA or compound C.RGC dendritic trees were 3D-reconstructed and analyzed with Imaris(Bitplane),and survival was assessed by counting Brn3a or RBPMS-labeled soma and axons in the optic nerve.RGC function was examined by quantification of anterograde axonal transport after intraocular administration of cholera toxinβ-subunit.Retinas from glaucoma patients were analyzed for expression of active AMPK.Results:Ocular hypertension triggered rapid upregulation of AMPK activity in RGCs concomitant with loss of mTORC1 function.AMPK inhibition with compound C or siRNA effectively restored mTORC1 activity and promoted an increase in total dendritic length,surface and complexity relative to control retinas.Attenuation of AMPK activity led to robust RGC soma and axon survival.For example,95%of RGCs(2,983±258 RGCs/mm2,mean±S.E.M.)survived with compound C compared to 77%in vehicle-treated eyes(2,430±233 RGCs/mm2)(ANOVA,P<0.001)at three weeks after glaucoma induction(n=8-10/group).Importantly,blockade of AMPK activity effectively restored anterograde axonal transport.Lastly,RGC-specific upregulation of AMPK activity was detected in human glaucomatous retinas relative to age-matched controls(n=10/group).Conclusions:Metabolic stress in glaucoma involves AMPK activation and mTORC1 inhibition promoting early RGC dendritic pathology,dysfunction and neurodegeneration.

Anti-hypertensive effects of rosiglitazone on renovascular hypertensive rats:role of oxidative stress and lipid metabolism

This study investigated the anti-hypertensive mechanismof rosiglitazone in renovascular hypertensive rats,and examined its relationship to oxidative stress and lipid metabolism. The renovascular hypertension was induced by stenosis of the left renal artery. Four groups of rats were selected： control,induced untreated,rosiglitazone（ 20 mg / kg） and captopril（ 10 mg / kg）. After 14 d of administration,compared with induced untreated group,rosiglitazone group reduced the renovascular hypertensive rats ＇ systolic blood pressure and diastolic blood pressure,and decreased total cholesterol（TCH）,triglyceride（TG）,angiotensin II（ Ang II） and angiotensin receptor（ AT1） levels（ P ＆lt; 0. 05）. Meanwhile,rosiglitazone remarkably decreased the levels of malondialdehyde（ MDA） and hydrogen peroxide（ H2O2） while improved the levels of supperoxide dismutase（ SOD） and reduced glutathione（ GSH）. These results suggested that rosiglitazone could effectively decreased the blood pressure in renovascular hypertensive rats,and this might be performed by regulating the activity of angiotensin and the lipid metabolismand improving the oxidative stress.

Deciphering the dual role and prognostic potential of PINK1 across cancer types

Metabolic rewiring and deregulation of the cell cycle are hallmarks shared by many cancers.Concerted mutations in key tumor suppressor genes,such as PTEN,and oncogenes predispose cancer cells for marked utilization of resources to fuel accelerated cell proliferation and chemotherapeutic resistance.Mounting research has demonstrated that PTEN-induced putative kinase 1(PINK1)acts as a pivotal regulator of mitochondrial homeostasis in several cancer types,a function that also extends to the regulation of tumor cell proliferative capacity.In addition,involvement of PINK1 in modulating inflammatory responses has been highlighted by recent studies,further expounding PINK1’s multifunctional nature.This review discusses the oncogenic roles of PINK1 in multiple tumor cell types,with an emphasis on maintenance of mitochondrial homeostasis,while also evaluating literature suggesting a dual oncolytic mechanism based on PINK1’s modulation of the Warburg effect.From a clinical standpoint,its expression may also dictate the response to genotoxic stressors commonly used to treat multiple malignancies.By detailing the evidence suggesting that PINK1 possesses distinct prognostic value in the clinical setting and reviewing the duality of PINK1 function in a context-dependent manner,we present avenues for future studies of this dynamic protein.

Oxidative metabolism of photosynthetic species and the exposure to some freshwater and marine biotoxins

Environmental climate conditions could lead to an increasing global occurrence of microorganism blooms that synthesize toxins in the aquatic environments.These blooms could result in significantly toxic events.Responses of photosynthetic organisms to adverse environmental conditions implicate reactive oxygen species generation;but,due to the presence of a varied cellular antioxidant defense system and complex signaling networks,this oxidative stress could act as an important factor in the environmental adaptive processes.The objective of this review was to assess how some biotoxins are implicated in the generation of oxidative and nitrosative metabolic changes,not only in biotoxin-producing organisms but also in non-producing organisms.Therefore,toxins may modify the oxidative cellular balance of several other species.Hence,the effect of toxins on the oxidative and nitrosative conditions will be evaluated in freshwater and marine algae and vascular plants.The changing climate conditions could act as agents capable of modifying the community composition leading to alterations in the global health of the habitat,risking the survival of many species with ecological relevance.

Hormonal and metabolic responses of fetal lamb during cardiopulmonary bypass

Objective To study the hormonal and metabolic responses of fetal lamb during cardiopulmonary bypass.Methods Six pregnant ewes underwent fetal cardiopulmonary bypasses with artificial oxygenators and roller pumps for 30 minutes,which maintained the blood gas value at the fetal physiological level. The fetal blood pressure,heart rate,pH value and blood lactate levels were monitored. The levels of catecholamine,cortisol and insulin were measured pre-bypass and then again 30 minutes later. The blood glucose and free fatty acid levels were monitored continuously during the bypass. Fetal hepatic PAS staining was also carried out.Results There were no changes before and during the bypass in fetal blood pressure,heart rate and blood gas. However,pH values decreased and blood lactate levels increased ( P <0.05). The fetal catecholamine and cortisol levels increased significantly ( P <0.01),while the levels of insulin did not change. The blood glucose and free fatty acid levels increased at the beginning of the bypass ( P <0.01),and then gradually slowed down during the bypass. The fetal hepatic PAS staining showed that hepatic glycogen was consumed in large amounts. After 30 minutes of bypass,the fetal lamb would not survive more than 1 hour.Conclusion The fetal lamb has a strong negative reaction to cardiopulmonary bypass.

Jiangtang Xiaoke granule attenuates glucose metabolism disorder via regulating endoplasmic reticulum stress in the liver of type 2 diabetes mellitus mice

OBJECTIVE:To observe the effect of Jiangtang Xiaoke(JTXK) granule on endoplasmic reticulum(ER)stress in high fat diet(HFD)-induced type 2 diabetes mellitus(T2 DM) KK-Ay mice.METHODS:KK-Ay mice were fed with HFD to induce the T2 DM model,while normal control C57 BL/6 J mice were given standard feed.Fasting blood glucose(FBG) in all mice was measured weekly and oral glucose tolerance tests(OGTTs) were performed at 4 and 10 weeks after start of treatment to determine glucose metabolism.Serum fasting insulin(FINS) and insulin sensitivity index(ISI) were measured to determine insulin sensitivity.m RNA expressions of eukaryotic initiation factor-2 alpha(e IF2α),glucose regulated protein 78(GRP78),activating transcription factor 4(ATF4),and C/EBP homology protein(CHOP) were assessed by reverse transcription polymerase chain reaction and the protein expressions of p-e IF2α,GRP78,and CHOP were assessed by Western blotting.RESULTS:JTXK granule significantly reduced FBG and free fatty acid levels and improved OGTT at the120 min of the 10-week treatment in T2 DM KK-Ay mice.FINS and Hb Alc levels were reduced and insulin sensitivities were increased in KK-Ay diabetic mice,which were improved with the treatment of JTXK granule,especially at the 7 and 3.5 g/kg doses.JTXK granule at the 3.5 g/kg dose was most effective in reducing both gene and protein expressions of e IF2α,GRP78,and CHOP.CONCLUSION:ER stress response is increased in T2 DM KK-Ay mice.Treatment with JTXK granule attenuates glucose disorders,improves insulin sensitivity,and reduces serum FFA in T2 DM KK-Ay mice.The mechanisms may be attributed to regulation of the signaling ER stress pathway via decreasing e IF2α phosphorylation and suppressing e IF2α-ATF4-CHOP activation.

LKB1 tumor suppressor: Therapeutic opportunities knock when LKB1 is inactivated

LKB1 is commonly thought of as a tumor suppressor gene because its hereditary mutation is responsible for a cancer syndrome,and somatic inactivation of LKB1 is found in nonsmall cell lung cancer,melanoma,and cervical cancers.However,unlike other tumor suppressors whose main function is to either suppress cell proliferation or promote cell death,one of the functions of LKB1-regulated AMPK signaling is to suppress cell proliferation in order to promote cell survival under energetic stress conditions.This unique,pro-survival function of LKB1 has led to the discovery of reagents,such as phenformin,that specifically exploit the vulnerability of LKB1-null cells in their defect in sensing energetic stress.Such targeted agents represent a novel treatment strategy because they induce cell killing when LKB1 is absent.This review article summarizes various vulnerabilities of LKB1-mutant cells that have been reported in the literature and discusses the potential of using existing or developing novel reagents to target cancer cells with defective LKB1.