Search

Gestational diabetes mellitus (GDM) is associated with a high-risk for metabolic complications in offspring. However, exercise is recognized as a non-pharmacological strategy against metabolic disorders and is recommended in GDM treatment. This study aimed to investigate whether gestational exercise (GE) could modulate maternal high-fat high-sucrose (HFHS) diet-related hepatic metabolic and mitochondrial outcomes in female offspring of mothers with HFHS-induced GDM. Female Sprague-Dawley rats were fed with control or HFHS diet and kept sedentary or submitted to GE. Their female offspring were fed with control diet and kept sedentary. Hepatic lipid accumulation, lipid metabolism regulators, mitochondrial biogenesis and dynamics markers, and microRNAs associated to the regulation of these markers were evaluated. Female offspring of GDM mothers showed increased body weight at early age, whereas GE prevented this effect of maternal HFHS-feeding and reduced hepatic lipid accumulation. GE stimulated hepatic mRNA transcription and protein expression of mitochondrial biogenesis markers (peroxisome proliferator-activated receptor-gamma co-activator-1alpha and mitochondrial transcription factor A) and mRNA transcription of mitochondrial dynamics markers (mitofusin-1, mitofusin-2, and dynamin-related protein-1) that were altered by maternal GDM, while mitochondrial dynamics markers protein expression was not affected by maternal diet/GE except for optic atrophy-1. MicroRNAs associated with these processes (miR-122, miR-34a, miR-130b, miR-494), and the expression of auto/mitophagy- and apoptosis-related proteins were not substantially influenced by altered intrauterine environment. Our findings suggest that GE is an important regulator of the intrauterine environment positively affecting liver metabolism and promoting liver mitochondrial biogenesis in female offspring despite eventual effects of maternal HFHS-feeding and related GDM. Highlights: Maternal lifestyle can affect hepatic metabolic status of their female offspring; Female offspring hepatic metabolism is affected by maternal high-fat/sucrose diet; Gestational exercise mitigated maternal diet-related harmful outcomes on offspring liver; Gestational exercise is an important regulator of offspring mitochondrial biogenesis and dynamics; Exercise programs should be encouraged in clinical counseling during pregnancy. This work was supported by the EU's Horizon 2020 Research and Innovation program under the Marie Skłodowska-Curie Actions (No.722619, FOIE GRAS; No.734719, mtFOIE GRAS) and by the Por tuguese Foundation for Science and Technology (FCT) (FCT/UID/DTP/00617/2020-base; POCI-01-0145-FEDER-016690-PTDC/DTP-DES/7087/2014; POCI-01-0145-FEDER-016657-PTDC/DTP-DES/1082/2014), to JB (SFRH/BD/129645/2017). info:eu-repo/semantics/publishedVersion

This article belongs to the Special Issue Targeting Mitochondria in Metabolic Diseases 2.0. Mothers' antenatal strategies to improve the intrauterine environment can positively decrease pregnancy-derived intercurrences. By challenging the mother-fetus unit, gestational exercise (GE) favorably modulates deleterious stimuli, such as high-fat, high-sucrose (HFHS) diet-induced adverse consequences for offspring. We aimed to analyze whether GE alters maternal HFHS-consumption effects on male offspring's maximal workload performance (MWP) and in some skeletal muscle (the soleus-SOL and the tibialis anterior-TA) biomarkers associated with mitochondrial biogenesis and oxidative fitness. Infant male Sprague-Dawley rats were divided into experimental groups according to mothers' dietary and/or exercise conditions: offspring of sedentary control diet-fed or HFHS-fed mothers (C-S or HFHS-S, respectively) and of exercised HFHS-fed mothers (HFHS-E). Although maternal HFHS did not significantly alter MWP, offspring from GE dams exhibited increased MWP. Lower SOL AMPk levels in HFHS-S were reverted by GE. SOL PGC-1α, OXPHOS C-I and C-IV subunits remained unaltered by maternal diet, although increased in HFHS-E offspring. Additionally, GE prevented maternal diet-related SOL miR-378a overexpression, while upregulated miR-34a expression. Decreased TA C-IV subunit expression in HFHS-S was reverted in HFHS-E, concomitantly with the downregulation of miR-338. In conclusion, GE in HFHS-fed dams increases the offspring's MWP, which seems to be associated with the intrauterine modulation of SM mitochondrial density and functional markers. Fundação para a Ciência e a Tecnologia, Grant/Award Number: POCI-01- 0145-FEDER 016657-PTDC/DTP- DES/1082/2014, POCI-01-0145-FEDER- 016690-PTDC/DTP-DES/7087/2014, SFRH/BD/129645/2017 and UIDB/00617/2020-base; H2020 Marie Skłodowska-Curie Actions, Grant/Award Number: 722619 and 734719. info:eu-repo/semantics/publishedVersion

Maternal high-caloric nutrition and related gestational diabetes mellitus (GDM) are relevant modulators of the intrauterine environment, increasing the risk of liver metabolic alterations in mothers and offspring. In contrast, as a non-pharmacological approach against metabolic disorders, exercise is highly recommended in GDM treatment. We analysed whether gestational exercise (GE) protects mothers from diet-induced GDM metabolic consequences and mitigates liver mitochondrial deleterious alterations in their 6-week-old male offspring. Female Sprague Dawley rats were fed with control or high-fat high-sucrose (HFHS) diet and kept sedentary or submitted to GE. Male offspring were sedentary and fed with control diet. Sedentary HFHS mothers and their offspring showed impaired hepatic mitochondrial biogenesis and morphological evidence of mitochondrial remodelling. In contrast, GE-related beneficial effects were demonstrated by upregulation of mitochondrial biogenesis signalling markers and mitochondrial fusion proteins and downregulation of mitochondrial fission protein. Alterations in miR-34a, miR-130b, and miR-494, associated with epigenetic regulation of mitochondrial biogenesis, suggested that GE is a more critical modulator of intergenerational changes in miRs expression than the maternal diet. Our data showed that GE positively modulated the altered hepatic mitochondrial biogenesis and dynamics markers and quality control signalling associated with maternal HFHS-diet-related GDM in mothers and offspring.

SPECIAL ISSUE: 'FOIEGRAS-Bioenergetic Remodelling in the Pathophysiology and Treatment of Non-Alcoholic Fatty Liver Disease'. Background Non-alcoholic fatty liver disease (NAFLD) emerges as significant health burden worldwide. Lifestyle changes, unhealthy dietary habits and physical inactivity, can trigger NAFLD development. Persisting on these habits during pregnancy affects in utero environment and prompts a specific metabolic response in foetus resulting in offspring metabolic maladjustments potentially critical for developing NAFLD later in life. The increasing prevalence of NAFLD, particularly in children, has shifted the research focus towards preventive and therapeutic strategies. Yet, designing effective approaches that can break the NAFLD intergenerational cycle becomes even more complicated. Regular physical exercise (PE) is a powerful non-pharmacological strategy known to counteract deleterious metabolic outcomes. In this narrative review, we aimed to briefly describe NAFLD pathogenesis focusing on maternal nutritional challenge and foetal programming, and to provide potential mechanisms behind the putative intergenerational effect of PE against metabolic diseases, including liver diseases. Methods Following detailed electronic database search, recent existing evidence about NAFLD development, intergenerational programming and gestational exercise effects was critically analysed and discussed. Results PE during pregnancy could have a great potential to counteract intergenerational transmission of metabolic burden. The interplay between different PE roles-metabolic, endocrine and epigenetic-could offer a more stable in utero environment to the foetus, thus rescuing offspring vulnerability to metabolic disturbances. Conclusions The better understanding of maternal PE beneficial consequences on offspring metabolism could reinforce the importance of PE during pregnancy as an indispensable strategy in improving offspring health.

'Special issue - In Utero and Early Life Programming of Aging and Disease'. Skeletal muscle (SM) adaptations to physical exercise (PE) have been extensively studied due, not only to the relevance of its in situ plasticity, but also to the SM endocrine-like effects in noncontractile tissues, such as brain, liver or adipocytes. Regular PE has been considered a pleiotropic nonpharmacological strategy to prevent and counteract the deleterious consequences of several metabolic, cardiovascular, oncological and neurodegenerative disorders. Additionally, PE performed by parents seems to have a direct impact in the offspring through the transgenerational programming of different tissues, such as SM. In fact, SM offspring programming mechanisms seems to be orchestrated, at least in part, by epigenetic machinery conditioning transcriptional or post-transcriptional processes. Ultimately, PE performed in the early in life is also a critical window of opportunity to positively modulate the juvenile and adult phenotype. Parental PE has a positive impact in several health-related offspring outcomes, such as SM metabolism, differentiation, morphology and ultimately in offspring exercise volition and endurance. Also, early-life PE counteracts conceptional-related adverse effects and induces long-lasting healthy benefits throughout adulthood. Additionally, epigenetics mechanisms seem to play a key role in the PE-induced SM adaptations. Despite the undoubtedly positive role of parental and early-life PE on SM phenotype, a strong research effort is still needed to better understand the mechanisms that positively regulate PE-induced SM programming.

Background Maternal high-caloric nutrition and related gestational diabetes mellitus (GDM) are associated with a high-risk for developing metabolic complications later in life and in their offspring. In contrast, exercise is recognized as a non-pharmacological strategy against metabolic dysfunctions associated to lifestyle disorders. Therefore, we investigated whether gestational exercise delays the development of metabolic alterations in GDM mothers later in life, but also protects 6-week-old male offspring from adverse effects of maternal diet. Methods Female Sprague-Dawley rats were fed with either control (C) or high-fat high-sucrose (HFHS) diet to induce GDM and submitted to gestational exercise during the 3 weeks of pregnancy. Male offspring were sedentary and fed with C-diet. Results Sedentary HFHS-fed dams exhibited increased gestational body weight gain (p

Significance: The prevalence and incidence of age-related neurodegenerative diseases (NDDs) tend to increase along with the enhanced average of the world life expectancy. NDDs are a major cause of morbidity and disability, affecting the health care, social and economic systems with a significant impact. Critical Issues and Recent Advances: Despite the worldwide burden of NDDs and the ongoing research efforts to increase the underlying molecular mechanisms involved in NDD pathophysiologies, pharmacological therapies have been presenting merely narrow benefits. On the contrary, absent of detrimental side effects but growing merits, regular physical exercise (PE) has been considered a prone pleiotropic nonpharmacological alternative able to modulate brain structure and function, thereby stimulating a healthier and "fitness" neurological phenotype. Future Directions: This review summarizes the state of the art of some peripheral and central-related mechanisms that underlie the impact of PE on brain plasticity as well as its relevance for the prevention and/or treatment of NDDs. Nevertheless, further studies are needed to better clarify the molecular signaling pathways associated with muscle contractions-related myokines release and its plausible positive effects in the brain. In addition, particular focus of research should address the role of PE in the modulation of mitochondrial metabolism and oxidative stress in the context of NDDs.

Aims Aging and drug-induced side effects may contribute to deteriorate mitochondrial bioenergetics in many tissues, including kidney and liver. One possibility is that the combination of both aging and drug toxicity accelerates the process of mitochondrial degradation, leading to progressive bioenergetic disruption. We therefore analyzed in vitro kidney (KM) and liver (LM) mitochondrial response to salicylate and diclofenac in old and adult animals. Main methods Male-Wistar adult (19-wks) and aged (106-wks) rats were used. In vitro endpoints of oxygen consumption and membrane potential were evaluated in non-treated conditions (vehicle) and in the presence of salicylate (0.5 mM) and diclofenac (50 μM). The susceptibility to calcium-induced permeability transition pore (MPTP) was assessed. Aconitase and C, –SH and MDA contents were measured. Apoptotic signaling was followed by measuring caspase 3, 8 and 9 activities, Bax, Bcl2 and CypD expression. ANT content was semi-quantified. Key findings In general, animal age alone compromised KM state 3 and LM ADP lag phase while resulting in decreased resistance to the MPTP. Aging decreased LM CypD and increased Mn-SOD. Kidney caspase 9-like activity was lower in aged group. Salicylate and diclofenac induced KM and LM dysfunction. ADP lag phase in KM was further increased in the aged group in the presence of diclofenac. No further impairments were observed regarding drug toxicity adding to the aging process. Significance Aging impaired KM and LM function despite no detected alterations on oxidative stress and apoptosis. However, aging did not further exacerbate KM and LM frailty induced by salicylate and diclofenac.

Several studies have been carried out to evaluate the alterations in mitochondrial functions of diabetic rats. However, results are sometimes controversial, since experimental conditions diverge, including age and strain of used animals. The purpose of this study was to evaluate the metabolic modifications in liver mitochondria, both in the presence of severe (STZ-treated rats) and mild hyperglycaemia [Goto–Kakizaki (GK) rats], when compared with control animals of similar age. Moreover, metabolic alterations were evaluated also at initial and advanced stages of the disease.We observed that both models of diabetes (type 1 and type 2) presented a decreased susceptibility of liver mitochondria to the induction of permeability transition (MPT). Apparently, there is a positive correlation between the severity of diabetes mellitus (and duration of the disease) and the decline in the susceptibility to MPT induction. We also found that liver mitochondria isolated from diabetic rats presented some metabolic adaptations, such as an increase in coenzyme Q and cardiolipin contents, that can be responsible for the observed decrease in the susceptibility to multiprotein pore (MPTP) opening.

Background Several strategies have been developed to counteract liver injury as a consequence of nonsteroid anti-inflammatory drugs toxicity. Here, we aimed to determine whether physical exercise results in liver mitochondrial protection against in vitro diclofenac toxicity. Material and methods Male adult Sprague-Dawley rats were divided into sedentary, 12-week endurance training (ET) and voluntary activity (VPA). In vitro liver mitochondrial function as assessed by oxygen consumption, transmembrane electric potential (ΔΨ) and susceptibility to the mitochondrial permeability transition pore (MPTP) was evaluated in the absence and presence of diclofenac. Mitochondrial oxidative stress markers [MnSOD, aconitase, -SH and MDA, SIRT3, p66shc(Ser36)/p66shc ratio] and apoptotic signalling (caspases 3, 8 and 9, Bax, Bcl-2 and CypD) were assessed. Content of OXPHOS components and qualitative liver morphological evaluation were assessed. Results Despite no effects of ET and VPA on basal liver mitochondrial oxygen consumption or ΔΨ endpoints, exercised animals showed lower susceptibility to MPTP. Diclofenac-induced decrease in ΔΨ, increased state 4 respiration and susceptibility to MPTP opening were all prevented by exercise. Under untreated conditions, VPA group showed higher aconitase activity, while ET decreased MDA and increased Bax content. VPA decreased p66shc(Ser36), complex III and V OXPHOS subunits. Both ET and VPA increased complex IV OXPHOS subunit, and SIRT3 and Bcl-2 content and decreased caspase 9 activity. Unexpectedly, ET and VPA decreased ANT. Conclusions Both chronic physical exercise models augmented the resistance to in vitro diclofenac-induced mitochondrial alterations, including increased MPTP susceptibility, possibly by modulating oxidative stress and MPTP regulators.

Carvedilol ([1-[carbazolyl-(4)-oxy]-3-[2-methoxyphenoxyethyl) amino]-propanol-(2)]) has been shown to protect cardiac mitochondria from oxidative stress. In this work we examined the mechanisms responsible for an observed depressive effect in the mitochondrial transmembrane potential (delta psi). Two possible mechanisms were considered: a protonophoretic activity and the opening of mitochondrial ATP-sensitive potassium channels. We show that carvedilol increases mitochondrial inner membrane permeability to protons, but not to potassium, causing an increase in state IV respiration in the presence and absence of oligomycin. By contrast, a K(ATP)-channel inhibitor, 5-hydroxydecanoic acid, did not affect carvedilol-induced depolarizations. Hence, our results suggest that carvedilol depresses mitochondrial delta psi by a weak protonophoretic mechanism.

The mitochondrial permeability transition is a widely studied, but poorly understood, phenomenon in mitochondrial bioenergetics. It has been recognised that this phenomenon is related to the opening of a protein pore in the inner mitochondrial membrane, and that opening of this pore is the cause of some forms of mitochondrial dysfunction. In this work, we propose that carvedilol, a multi-role cardioprotective compound, may act as an inhibitor of the high-conductance state of the mitochondrial permeability transition pore, a conclusion supported by the finding that carvedilol provides differential protection against mitochondrial swelling in sucrose and KCl-based media, and that it is unable to protect against calcium-induced depolarisation of the mitochondrial membrane. We also show that carvedilol inhibits the oxidation of mitochondrial thiol groups and that, beyond causing a slight depression of the membrane potential, it has no inhibitory effect on mitochondrial calcium uptake. A decrease in the number of oxidised protein thiol groups may be the main mechanism responsible for this selective inhibition of the permeability transition pore in heart mitochondria. These effects may be important for the role of carvedilol in some cardiac pathologies.

Aging and drug-induced side effects may contribute to the deterioration of mitochondrial bioenergetics in the brain. One hypothesis is that the combination of both deleterious stimuli accelerates the process of mitochondrial degradation, leading to progressive bioenergetic disruption. The hypothesis was tested by analyzing the isolated and combined effect of aging and salicylate, a vastly used anti-inflammatory drug, on isolated brain fractions in rats. Male Wistar rats were divided according to age in two groups: adult ( n = 8, 19 weeks of age) and aged ( n = 8, 106 weeks of age). In vitro endpoints of brain mitochondrial function including oxygen consumption and transmembrane electric potential (Δ Ψ ) were evaluated in the absence and in the presence of salicylate (0.5 mM). Brain mitochondrial susceptibility to calcium-induced permeability transition pore (MPTP) was also assessed. Mitochondrial oxidative stress was determined by measuring aconitase and manganese-superoxide dismutase (SOD) activity, and content in sulfhydryl groups ( SH) and malondialdehyde (MDA). Mitochondrial content in apoptotic-related proteins Bax, Bcl-2 and cyclophilin D was determined by Western Blotting. Under basal, untreated, conditions, aging affected brain mitochondrial state 3 respiration, maximal Δ Ψ developed, ADP phosphorylation lag phase and calcium-induced MPTP. Interestingly, MDA decreased and Mn-SOD activity increased in the aged group. Brain mitochondrial Bcl-2 content decreased and Bax/Bcl-2 ratio increased in aged group. Salicylate incubation for 20 min increased lipid peroxidation in the aged group only and stimulated respiration during state 2, accompanied by decreased Δ Ψ , although both effects were independent of the animal age. We confirmed that both aging and salicylate per se impaired brain mitochondrial bioenergetics, although the combination of both does not seem to worsen the mitochondrial end-points studied.

Cholestasis and other liver diseases may affect the heart through the toxic effects of the retained bile acids on cardiac mitochondria, which could explain the origin of hepatic-derived cardiomyopathies. The objective of this work was to test the hypothesis that bile acids are toxic to heart mitochondria for concentrations that are relevant for cholestasis. Heart mitochondria were isolated from rat and subjected to incubation with selected bile acids (litocholic acid [LCA], deoxycholic acid [DCA], chenodeoxycholic acid [CDCA], glycochenodeoxycholic acid [GCDC], taurodeoxycholic acid [TDCA], and glycoursodeoxycholic acid [GUDC]). We observed that the most toxic bile acids were also the most lipophilic ones (LCA, DCA, and CDCA), inducing a decrease on state 3 respiration, respiratory control ratio, and membrane potential and causing the induction of the mitochondrial permeability transition. GUDC was the bile acid with lower indexes of toxicity on isolated heart mitochondria. The results of this research indicate that at toxicologically relevant concentrations, most bile acids (mainly the most lipophilic) alter mitochondrial bioenergetics. The impairment of cardiac mitochondrial function may be an important cause for the observed cardiac alterations during cholestasis.

Background Modern lifestyles, especially high-caloric intake and physical inactivity, contribute to the increased prevalence of non-alcoholic fatty liver disease (NAFLD), which becomes a significant health problem worldwide. Lifestyle changes, however, affect not only parental generation, but also their offspring, reinforcing the need for efficient preventive approaches to deal with this disease. This transgenerational influence of phenotypes dependent on parents (particularly maternal) behaviours may open additional research avenues. Despite persistent attempts to design an effective pharmacological therapy against NAFLD, physical activity, as a non-pharmacological approach, emerges as an exciting strategy. Scope of Review Here we briefly review the effect of physical exercise on liver mitochondria adaptations in NAFLD, highlighting the importance of mitochondrial metabolism and transgenerational and epigenetic mechanisms in liver diseases. Major Conclusions A deeper look into cellular mechanisms sheds a light on possible effects of physical activity in the prevention and treatment of NAFLD through modulation of function and structure of particular organelles, namely mitochondria. Additionally, despite of increasing evidence regarding the contribution of epigenetic mechanisms in the pathogenesis of different diseases, the role of microRNAs, DNA methylation, and histone modification in NAFLD pathogenesis still needs to be elucidated., Highlights • Modern lifestyle, including physical inactivity, contribute to NAFLD development. • Maternal lifestyle through epigenetic mechanisms may influence offspring health. • Exercise is a potential protective non-pharmacological strategy against NAFLD. • Exercise can modulate liver mitochondrial structure and function. • Exercise-related epigenetic mechanisms may explain exercise role in NAFLD treatment.