Physical exercise for individuals with dementia: potential benefits perceived by formal caregivers.

BACKGROUND: The social and economic impact of dementia for the development of accessible and sustainable care for individuals with dementia (IwD). Physical exercise has been seen as a beneficial non-pharmacological therapy in the prevention and management of dementia, and possible benefits may not only impact on participants, but also indirectly on their caregivers. Thus, this quasi-experimental non-randomized study aimed to analyze the effects of an exercise intervention on functional capacity, behavioural and psychological symptoms in dementia (BPSD) and quality of life of institutionalized older adults with dementia, perceived by their formal caregivers. METHODS: Sixty-four institutionalized older adults (from both genders, aged 65-93 yrs. old), clinically diagnosed with dementia, were divided into two groups: control group (CG, continued with usual care, n = 26) and exercise group (EG, 6-month supervised multicomponent exercise intervention, n = 38). Nine caregivers (female, aged 28-47 yrs. old) from nine different nursing homes, reported about their distress related to BPSD and proxy-reported about participants' functional capacity (Katz index), quality of life (QoL-AD), BPSD (NPI) before and after 6 months of an exercise intervention (aerobic, muscular resistance, flexibility and postural exercises). RESULTS: A two-way ANOVA, with repeated measures, revealed significant group and time interactions on Total Katz index and QoL-AD. The CG's performance functional capacity and quality of life score worsen over time while in EG maintains these values after the exercise intervention. Moreover, formal caregiver's distress triggered by apathy and disinhibition increased in CG while after 6 months of an exercise intervention no alterations were seen regarding these distress causes in EG. No significant main effects were observed for total NPI score or NPI distress. CONCLUSIONS: Overall results show that after the exercise intervention, IwD from the EG, was capable of preserving the functional capacity, quality of life and neuropsychiatric symptoms were attenuate, contributing to a lower load of distress for the caregivers. TRIAL REGISTRATION: clinicaltrials.gov , NCT04095962 . Retrospectively registered on 19 September 2019.

Physical fitness in institutionalized older adults with dementia: association with cognition, functional capacity and quality of life.

This cross-sectional study investigated the association of physical fitness with cognitive function, functional capacity and quality of life among institutionalized older adults with dementia. One hundred and two older adults aged 78.0 ± 8.4 years, predominantly female (67.6%), with neurocognitive disorder due to Alzheimer's disease (AD) (49.2%), vascular dementia (14.7%), Parkinson's disease (2%), dementia with Lewy bodies (2%) or unspecified dementia (32.1%) participated in the present study. Regression analyses were used to examine associations between physical fitness components (Senior Fitness Test) and cognitive function (Mini-Mental State Examination), functional capacity (Katz Index of Independence in Activities of Daily Living) and Quality of Life (QoL)-Alzheimer's Disease scale. Univariate regression indicates that strength, flexibility, agility/dynamic balance and aerobic endurance are relevant for cognitive function, physical capacity and perceived QoL in institutionalized older people with dementia. After multiple regression analyses, adjusted for body mass index (BMI), results showed that aerobic endurance had a significant positive association with Total Katz Index. For both, caregiver perception of QoL-AD and global QoL-AD, BMI remained significantly and positively associated. Agility-dynamic balance presented a significant negative relation with global QoL-AD. Overall, our findings suggest that better physical fitness is important for cognition and autonomous functional capacity and that it has positive repercussions on the QoL in institutionalized older adults with dementia. Consequently, exercise-based therapeutic strategies aiming to improve physical fitness should be implemented.

The beneficial role of exercise in mitigating doxorubicin-induced Mitochondrionopathy.

Doxorubicin (DOX) is a widely used antineoplastic agent for a wide range of cancers, including hematological malignancies, soft tissue sarcomas and solid tumors. However, DOX exhibits a dose-related toxicity that results in life-threatening cardiomyopathy. In addition to the heart, there is evidence that DOX toxicity extends to other organs. This general toxicity seems to be related to mitochondrial network structural, molecular and functional impairments. Several countermeasures for these negative effects have been proposed, being physical exercise, not only one of the most effective non-pharmacologic strategy but also widely recommended as booster against cancer-related fatigue. It is widely accepted that mitochondria are critical sensors of tissue functionality, both modulated by DOX and exercise. Therefore, this review focuses on the current understanding of the mitochondrial-mediated mechanisms underlying the protective effect of exercise against DOX-induced toxicity, not only limited to the cardiac tissue, but also in other tissues such as skeletal muscle, liver and brain. We here analyze recent developments regarding the beneficial effects of exercise targeting mitochondrial responsive phenotypes against redox changes, mitochondrial bioenergetics, apoptotic, dynamics and quality control signalling affected by DOX treatment.

Exercise and Doxorubicin Treatment Modulate Cardiac Mitochondrial Quality Control Signaling.

The cross-tolerance effect of exercise against heart mitochondrial-mediated quality control, remodeling and death-related mechanisms associated with sub-chronic Doxorubicin (DOX) treatment is yet unknown. We therefore analyzed the effects of two distinct chronic exercise models (endurance treadmill training-TM and voluntary free wheel activity-FW) performed during the course of the sub-chronic DOX treatment on mitochondrial susceptibility to permeability transition pore (mPTP), apoptotic and autophagic signaling and mitochondrial dynamics. Male Sprague-Dawley rats were divided into six groups (n = 6 per group): saline sedentary (SAL + SED), SAL + TM (12-weeks treadmill), SAL + FW (12-weeks voluntary free-wheel), DOX + SED [7-weeks sub-chronic DOX treatment (2 mg kg-1 week-1)], DOX + TM and DOX + FW. Apoptotic signaling and mPTP regulation were followed by measuring caspase 3, 8 and 9 activities, Bax, Bcl2, CypD, ANT, and cophilin expression. Mitochondrial dynamics (Mfn1, Mfn2, OPA1 and DRP1) and auto(mito)phagy (LC3, Beclin1, Pink1, Parkin and p62)-related proteins were semi-quantified. DOX treatment results in augmented mPTP susceptibility and apoptotic signaling (caspases 3, 8 and 9 and Bax/Bcl2 ratio). Moreover, DOX decreased the expression of fusion-related proteins (Mfn1, Mfn2, OPA1), increased DRP1 and the activation of auto(mito)phagy signaling. TM and FW prevented DOX-increased mPTP susceptibility and apoptotic signaling, alterations in mitochondrial dynamics and inhibits DOX-induced increases in auto(mito)phagy signaling. Collectively, our results suggest that both used chronic exercise models performed before and during the course of sub-chronic DOX treatment limit cardiac mitochondrial-driven apoptotic signaling and regulate alterations in mitochondrial dynamics and auto(mito)phagy in DOX-treated animals.

Physical Exercise and Brain Mitochondrial Fitness: The Possible Role Against Alzheimer's Disease.

Exercise is one of the most effective strategies to maintain a healthy body and mind, with particular beneficial effects of exercise on promoting brain plasticity, increasing cognition and reducing the risk of cognitive decline and dementia in later life. Moreover, the beneficial effects resulting from increased physical activity occur at different levels of cellular organization, mitochondria being preferential target organelles. The relevance of this review article relies on the need to integrate the current knowledge of proposed mechanisms, focus mitochondria, to explain the protective effects of exercise that might underlie neuroplasticity and seeks to synthesize these data in the context of exploring exercise as a feasible intervention to delay cognitive impairment associated with neurodegenerative conditions, particularly Alzheimer disease.

Physical exercise mitigates doxorubicin-induced brain cortex and cerebellum mitochondrial alterations and cellular quality control signaling.

Doxorubicin (DOX) is a highly effective anti-neoplastic agent, whose clinical use is limited by a dose-dependent mitochondrial toxicity in non-target tissues, including the brain. Here we analyzed the effects of distinct exercise modalities (12-week endurance treadmill-TM or voluntary free-wheel activity-FW) performed before and during sub-chronic DOX treatment on brain cortex and cerebellum mitochondrial bioenergetics, oxidative stress, permeability transition pore (mPTP), and proteins involved in mitochondrial biogenesis, apoptosis and auto(mito)phagy. Male Sprague-Dawley rats were divided into saline-sedentary (SAL+SED), DOX-sedentary (DOX+SED; 7-week DOX (2 mg · kg(-1)per week)), DOX+TM and DOX+FW. Animal behavior and post-sacrifice mitochondrial function were assessed. Oxidative phosphorylation (OXPHOS) subunits, oxidative stress markers or related proteins (SIRT3, p66shc, UCP2, carbonyls, MDA, -SH, aconitase, Mn-SOD), as well as proteins involved in mitochondrial biogenesis (PGC1α and TFAM) were evaluated. Apoptotic signaling was followed through caspases 3, 8 and 9-like activities, Bax, Bcl2, CypD, ANT and cofilin expression. Mitochondrial dynamics (Mfn1, Mfn2, OPA1 and DRP1) and auto(mito)phagy (LC3II, Beclin1, Pink1, Parkin and p62)-related proteins were measured by semi-quantitative Western blotting. DOX impaired behavioral performance, mitochondrial function, including lower resistance to mPTP and increased apoptotic signaling, decreased the content in OXPHOS complex subunits and increased oxidative stress in brain cortex and cerebellum. Molecular markers of mitochondrial biogenesis, dynamics and autophagy were also altered by DOX treatment in both brain subareas. Generally, TM and FW were able to mitigate DOX-related impairments in brain cortex and cerebellum mitochondrial activity, mPTP and apoptotic signaling. We conclude that the alterations in mitochondrial biogenesis, dynamics and autophagy markers induced by exercise performed before and during treatment may contribute to the observed protective brain cortex and cerebellum mitochondrial phenotype, which is more resistant to oxidative damage and apoptotic signaling in sub-chronically DOX treated animals.

Exercise modulates liver cellular and mitochondrial proteins related to quality control signaling.

AIMS: The effects of exercise on cardiac and skeletal muscle, including the increase on mitochondrial function, dynamics, biogenesis and autophagy signaling are well described. However, these same effects on liver mitochondria, important in the context of hepatocyte ability to mitigate drug-induced injury and obesity-related disorders, are not fully understood. Therefore, the effects of two distinct chronic exercise models (endurance training--ET and voluntary physical activity--VPA) on liver cellular and mitochondrial quality control were analyzed. MAIN METHODS: Eighteen male-adult Sprague-Dawley rats were divided into sedentary (SED), ET (12-week treadmill) and VPA (12-week voluntary free wheel). Liver mitochondrial alterations were evaluated by semi-quantification of proteins involved in oxidative stress (SIRT3, p66shc, p66(Ser36)), biogenesis (citrate synthase, PGC-1α and mtTFA), dynamics (MFN1, OPA1 and DRP1) and auto(mito)phagy (Beclin-1, Bcl-2, LC3II/LC3I, p62, Parkin and PINK) signaling. Liver ultrastructural alterations were also evaluated. KEY FINDINGS: Both exercise models induced beneficial alterations on liver mitochondrial morphology and increased mitochondrial biogenesis (PGC-1α and mtTFA), autophagy-related proteins (Beclin-1, LC3-II, LC3II/LC3I), and DRP1 and SIRT3 proteins. Increased citrate synthase activity and OPA1, p62 and Parkin content as well as decreased PINK protein levels were only observed after ET. VPA decreased OPA1, Beclin-1/Bcl-2, Parkin and p66(Ser36). Mitochondrial density and circularity increased in both exercised groups. SIGNIFICANCE: Both chronic exercise models increased proteins related with mitochondrial biogenesis and alteration proteins involved in mitochondrial dynamics and autophagy signaling, suggesting that exercise can induce liver mitochondrial adaptive remodeling and hepatocyte renewal.

Physical exercise improves brain cortex and cerebellum mitochondrial bioenergetics and alters apoptotic, dynamic and auto(mito)phagy markers.

We here investigate the effects of two exercise modalities (endurance treadmill training-TM and voluntary free-wheel activity-FW) on the brain cortex and cerebellum mitochondrial bioenergetics, permeability transition pore (mPTP), oxidative stress, as well as on proteins involved in mitochondrial biogenesis, apoptosis, and quality control. Eighteen male rats were assigned to sedentary-SED, TM and FW groups. Behavioral alterations and ex vivo brain mitochondrial function endpoints were assessed. Proteins involved in oxidative phosphorylation (OXPHOS, including the adenine nucleotide translocator), oxidative stress markers and regulatory proteins (SIRT3, p66shc, UCP2, carbonyls, MDA, -SH, aconitase, Mn-SOD), as well as proteins involved in mitochondrial biogenesis (PGC1α, TFAM) were evaluated. Apoptotic signaling was measured through quantifying caspase 3, 8 and 9-like activities, Bax, Bcl2, CypD, and cofilin expression. Mitochondrial dynamics (Mfn1/2, OPA1 and DRP1) and auto(mito)phagy (LC3II, Beclin1, Pink1, Parkin, p62)-related proteins were also measured by Western blotting. Only the TM exercise group showed increased spontaneous alternation and exploratory activity. Both exercise regimens improved mitochondrial respiratory activity, increased OXPHOS complexes I, III and V subunits in both brain subareas and decreased oxidative stress markers. Increased resistance to mPTP and decreased apoptotic signaling were observed in the brain cortex from TM and in the cerebellum from TM and FW groups. Also, exercise increased the expression of proteins involved in mitochondrial biogenesis, autophagy and fusion, simultaneous with decreased expression of mitochondrial fission-related protein DRP1. In conclusion, physical exercise improves brain cortex and cerebellum mitochondrial function, decreasing oxidative stress and apoptotic related markers. It is also possible that favorable alterations in mitochondrial biogenesis, dynamics and autophagy signaling induced by exercise contributed to increased mitochondrial plasticity leading to a more robust phenotype.

Modulation of cardiac mitochondrial permeability transition and apoptotic signaling by endurance training and intermittent hypobaric hypoxia.

BACKGROUND: Modulation of the mitochondrial permeability transition pore (MPTP) and inhibition of the apoptotic signaling are critically associated with the cardioprotective phenotypes afforded by both intermittent hypobaric-hypoxia (IHH) and endurance-training (ET). We recently proposed that IHH and ET improve cardiac function and basic mitochondrial capacity, although without showing addictive effects. Here we investigate whether a combination of IHH and ET alters cardiac mitochondrial vulnerability to MPTP and related apoptotic signaling. METHODS: Male Wistar rats were divided into normoxic-sedentary (NS), normoxic-exercised (NE, 1h/day/5 week treadmill-running), hypoxic-sedentary (HS, 6000 m, 5h/day/5 weeks) and hypoxic-exercised (HE) to study susceptibility to calcium-induced cardiac MPTP opening. Mitochondrial cyclophilin D (CypD), adenine nucleotide translocator (ANT), Bax and Bcl-2 protein contents were semi-quantified by Western blotting. Cardiac caspase 3-, 8- and 9-like activities were measured. Mitochondrial aconitase and superoxide dismutase (MnSOD) activity and malondialdehyde (MDA) and sulphydryl group (-SH) content were determined. RESULTS: Susceptibility to MPTP decreased in NE and HS vs. NS and even further in HE. The ANT content increased in HE vs. NS. Bcl-2/Bax ratio increased in NE and HS compared to NS. Decreased activities in tissue caspase 3-like (HE vs. NS) and caspase 9-like (HS and HE vs. NS) were observed. Mitochondrial aconitase increased in NE and HS vs. NS. No alterations between groups were observed for caspase 8-like activity, MnSOD, CypD, MDA and -SH. CONCLUSIONS: Data confirm that IHH and ET modulate cardiac mitochondria to a protective phenotype characterized by decreased MPTP induction and apoptotic signaling, although without visible addictive effects as initially hypothesized.

Synergistic impact of endurance training and intermittent hypobaric hypoxia on cardiac function and mitochondrial energetic and signaling.

BACKGROUND: Intermittent hypobaric-hypoxia (IHH) and endurance-training (ET) are cardioprotective strategies against stress-stimuli. Mitochondrial modulation appears to be an important step of the process. This study aimed to analyze whether a combination of these approaches provides additive or synergistic effects improving heart-mitochondrial and cardiac-function. METHODS: Two-sets of rats were divided into normoxic-sedentary (NS), normoxic-exercised (NE, 1 h/day/5 weeks treadmill-running), hypoxic-sedentary (HS, 6000 m, 5h/day/5 weeks) and hypoxic-exercised (HE) to study overall cardiac and mitochondrial function. In vitro cardiac mitochondrial oxygen consumption and transmembrane potential were evaluated. OXPHOS subunits and ANT protein content were semi-quantified by Western blotting. HIF-1α, VEGF, VEGF-R1 VEGF-R2, BNP, SERCA2a and PLB expressions were measured by qRT-PCR and cardiac function was characterized by echocardiography and hemodynamic parameters. RESULTS: Respiratory control ratio (RCR) increased in NE, HS and HE vs. NS. Susceptibility to anoxia/reoxygenation-induced dysfunction decreased in NE, HS and HE vs. NS. HS decreased mitochondrial complex-I and -II subunits; however HE completely reverted the decreased content in complex-II subunits. ANT increased in HE. HE presented normalized ventricular-arterial coupling (Ea) and BNP myocardial levels and significantly improved myocardial performance as evaluated by increased cardiac output and normalization of the Tei index vs. HS CONCLUSION: Data demonstrates that IHH and ET confer cardiac mitochondria with a more resistant phenotype although without visible addictive effects at least under basal conditions. It is suggested that the combination of both strategies, although not additive, results into improved cardiac function.

Endurance training and chronic intermittent hypoxia modulate in vitro salicylate-induced hepatic mitochondrial dysfunction.

Mitochondrial function is modulated by multiple approaches including physical activity, which can afford cross-tolerance against a variety of insults. We therefore aimed to analyze the effects of endurance-training (ET) and chronic-intermittent hypobaric-hypoxia (IHH) on liver mitochondrial bioenergetics and whether these effects translate into benefits against in vitro salicylate mitochondrial toxicity. Twenty-eight young-adult male rats were divided into normoxic-sedentary (NS), normoxic-exercised (NE), hypoxic-sedentary (HS) and hypoxic-exercised (HE). ET consisted of 1h/days of treadmill running and IHH of simulated atmospheric pressure of 49.3 kPa 5h/days during 5weeks. Liver mitochondrial oxygen consumption, transmembrane-electric potential (ΔΨ) and permeability transition pore induction (MPTP) were evaluated in the presence and absence of salicylate. Aconitase, MnSOD, caspase-3 and 8 activities, SH, MDA, SIRT3, Cyp D, HSP70, and OXPHOS subunit contents were assessed. ET and IHH decreased basal mitochondrial state-3 and state-4 respiration, although no alterations were observed in ΔΨ endpoints evaluated in control mitochondria. In the presence of salicylate, ET and IHH decreased state-4 and lag-phase of ADP-phosphorylation. Moreover, ADP-lag phase in hypoxic was further lower than in normoxic groups. Neither ET nor IHH altered the susceptibility to calcium-induced MPTP. IHH lowered MnSOD and increased aconitase activities. ET and IHH decreased caspase 8 activity whereas no effect was observed on caspase 3. The levels of SIRT3 increased with ET and IHH and Cyp D decreased with IHH. Data suggest that ET and IHH do not alter general basal liver mitochondrial function, but may attenuate some adverse effects of salicylate.

In vitro salicylate does not further impair aging-induced brain mitochondrial dysfunction.

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 (ΔΨ) were evaluated in the absence and in the presence of salicylate (0.5mM). 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 ΔΨ 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 20min increased lipid peroxidation in the aged group only and stimulated respiration during state 2, accompanied by decreased ΔΨ, 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.