Mitochondria are negatively affected by ageing leading to their inability to adapt to higher levels of oxidative stress and this ultimately contributes to the systemic loss of muscle mass and ...function termed sarcopenia. Since mitochondria are central mediators of muscle health, they have become highly sought‐after targets of physiological and pharmacological interventions. Exercise is the only known strategy to combat sarcopenia and this is largely mediated through improvements in mitochondrial plasticity. More recently a critical role for mitochondrial turnover in preserving muscle has been postulated. Specifically, cellular pathways responsible for the regulation of mitochondrial turnover including biogenesis, dynamics and autophagy may become dysregulated during ageing resulting in the reduced clearance and accumulation of damaged organelles within the cell. When mitochondrial quality is compromised and homeostasis is not re‐established, myonuclear cell death is activated and muscle atrophy ensues. In contrast, acute and chronic exercise attenuates these deficits, restoring mitochondrial turnover and promoting a healthier mitochondrial pool that leads to the preservation of muscle. Additionally, the magnitude of these exercise‐induced mitochondrial adaptations is currently debated with several studies reporting a lower adaptability of old muscle relative to young, but the processes responsible for this diminished training response are unclear. Based on these observations, understanding the molecular details of how advancing age and exercise influence mitochondria in older muscle will provide invaluable insight into the development of exercise protocols that will maximize beneficial adaptations in the elderly. This information will also be imperative for future research exploring pharmacological targets of mitochondrial plasticity.
Mitochondria produce reactive oxygen species (ROS) during normal respiration, but when these free radicals accumulate, this leads to progressive damage to mitochondrial constituents including DNA, proteins and lipids. Mitochondrial DNA (mtDNA) mutations impair the synthesis of electron transport chain subunits and reduce oxidative phosphorylation. These changes cause mitochondrial dysfunction that affects a number of pathways vital for maintaining mitochondrial turnover and integrity such as biogenesis, dynamics (fusion and fission), autophagy–lysosomal degradation, and programmed cell death (apoptosis). Additionally, mitochondrial dysfunction through a vicious cycle causes further increases in ROS and oxidative damage, ultimately leading to a decline in muscle mass and strength, reduced physical function, and ageing.
ABSTRACT
Introduction: The mitochondrial network within cells is mediated by fission and fusion processes. Methods: We investigated the expression of the proteins responsible for these events during ...conditions of altered oxidative capacity. Results: With chronic contractile activity, the mitochondrial reticulum increased in size, along with concomitant increases in the fusion proteins Opa1 and Mfn2 (by 36% and 53%; P < 0.05). When we induced muscle disuse through denervation for 7 days, fragmented mitochondria were observed, along with significant decreases in the expression of Mfn2 and Opa1 (by 84% and 70%). To assess the effects of aging on mitochondrial morphology, young (5 month) and aged (35 month) Fisher 344 Brown Norway rats were used. Aged animals also possessed smaller mitochondria and displayed increased levels of fission proteins. Conclusions: Chronic muscle use increases the ratio of fusion:fission proteins, leading to reticular mitochondria, whereas muscle disuse and aging result in a decrease in this ratio, culminating in fragmented organelles. Muscle Nerve 48: 963–970, 2013
ICTV Virus Taxonomy Profile: Parvoviridae Cotmore, Susan F; Agbandje-McKenna, Mavis; Canuti, Marta ...
Journal of general virology,
03/2019, Letnik:
100, Številka:
3
Journal Article
Recenzirano
Odprti dostop
Members of the family Parvoviridae are small, resilient, non-enveloped viruses with linear, single-stranded DNA genomes of 4-6 kb. Viruses in two subfamilies, the Parvovirinae and Densovirinae, are ...distinguished primarily by their respective ability to infect vertebrates (including humans) versus invertebrates. Being genetically limited, most parvoviruses require actively dividing host cells and are host and/or tissue specific. Some cause diseases, which range from subclinical to lethal. A few require co-infection with helper viruses from other families. This is a summary of the International Committee on Taxonomy of Viruses (ICTV) Report on the Parvoviridae, which is available at www.ictv.global/report/parvoviridae.
• Cell wall fibre and lamina density may interactively affect leaf toughness and leaf lifespan. Here, we tested this with seedlings of 24 neotropical tree species differing in shade tolerance and ...leaf lifespan under standardized field conditions (140–867 d in gaps; longer in shade). We quantified toughness with a cutting test, explicitly seeking a mechanistic linkage to fibre. • Lamina density, but not fracture toughness, exhibited a plastic response to gaps vs shade, while neither trait was affected by leaf age. Toughness corrected for lamina density, a recently recognized indicator of material strength per unit mass, was linearly correlated with cellulose content per unit dry mass. • Leaf lifespan was positively correlated with cellulose and toughness in shade‐tolerant species but only weakly in gap‐dependent species. Leaf lifespan was uncorrelated with lamina thickness, phenolics and tannin concentrations. In path analysis including all species, leaf lifespan was directly enhanced by density and toughness, and indirectly by cellulose via its effect on toughness. Different suites of leaf traits were correlated with early seedling survival in gaps vs shade. • In conclusion, cellulose and lamina density jointly enhance leaf fracture toughness, and these carbon‐based physical traits, rather than phenolic‐based defence, explain species differences in herbivory, leaf lifespan and shade survival.
Summary
Age‐related loss of muscle mass and strength (sarcopenia) leads to a decline in physical function and frailty in the elderly. Among the many proposed underlying causes of sarcopenia, ...mitochondrial dysfunction is inherent in a variety of aged tissues. The intent of this study was to examine the effect of aging on key groups of regulatory proteins involved in mitochondrial biogenesis and how this relates to physical performance in two groups of sedentary elderly participants, classified as high‐ and low‐functioning based on the Short Physical Performance Battery test. Muscle mass was decreased by 38% and 30% in low‐functioning elderly (LFE) participants when compared to young and high‐functioning elderly participants, respectively, and positively correlated to physical performance. Mitochondrial respiration in permeabilized muscle fibers was reduced (41%) in the LFE group when compared to the young, and this was associated with a 30% decline in cytochrome c oxidase activity. Levels of key metabolic regulators, SIRT3 and PGC‐1α, were significantly reduced (50%) in both groups of elderly participants when compared to young. Similarly, the fusion protein OPA1 was lower in muscle from elderly subjects; however, no changes were detected in Mfn2, Drp1 or Fis1 among the groups. In contrast, protein import machinery components Tom22 and cHsp70 were increased in the LFE group when compared to the young. This study suggests that aging in skeletal muscle is associated with impaired mitochondrial function and altered biogenesis pathways and that this may contribute to muscle atrophy and the decline in muscle performance observed in the elderly population.
Mitochondrial DNA (mtDNA) mutations lead to decrements in mitochondrial function and accelerated rates of these mutations has been linked to skeletal muscle loss (sarcopenia). The purpose of this ...study was to investigate the effect of mtDNA mutations on mitochondrial quality control processes in skeletal muscle from animals (young; 3-6 months and older; 8-15 months) expressing a proofreading-deficient version of mtDNA polymerase gamma (PolG). This progeroid aging model exhibits elevated mtDNA mutation rates, mitochondrial dysfunction, and a premature aging phenotype that includes sarcopenia. We found increased expression of the mitochondrial biogenesis regulator peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α) and its target proteins, nuclear respiratory factor 1 (NRF-1) and mitochondrial transcription factor A (Tfam) in PolG animals compared to wild-type (WT) (P<0.05). Muscle from older PolG animals displayed higher mitochondrial fission protein 1 (Fis1) concurrent with greater induction of autophagy, as indicated by changes in Atg5 and p62 protein content (P<0.05). Additionally, levels of the Tom22 import protein were higher in PolG animals when compared to WT (P<0.05). In contrast, muscle from normally-aged animals exhibited a distinctly different expression profile compared to PolG animals. Older WT animals appeared to have higher fusion (greater Mfn1/Mfn2, and lower Fis1) and lower autophagy (Beclin-1 and p62) compared to young WT suggesting that autophagy is impaired in aging muscle. In conclusion, muscle from mtDNA mutator mice display higher mitochondrial fission and autophagy levels that likely contribute to the sarcopenic phenotype observed in premature aging and this differs from the response observed in normally-aged muscle.
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Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Glucocorticoids are steroid hormones that regulate inflammation, growth, metabolism, and apoptosis via their cognate receptor, the glucocorticoid receptor (GR). GR, acting mainly as a transcription ...factor, activates or represses the expression of a large number of target genes, among them, many genes of anti-inflammatory and pro-inflammatory molecules, respectively. Transrepression activity of glucocorticoids also accounts for their anti-inflammatory activity, rendering them the most widely prescribed drug in medicine. However, chronic and high-dose use of glucocorticoids is accompanied with many undesirable side effects, attributed predominantly to GR transactivation activity. Thus, there is a high need for selective GR agonist, capable of dissociating transrepression from transactivation activity. Protopanaxadiol and protopanaxatriol are triterpenoids that share structural and functional similarities with glucocorticoids. The molecular mechanism of their actions is unclear. In this study applying induced-fit docking analysis, luciferase assay, immunofluorescence, and Western blot analysis, we showed that protopanaxadiol and more effectively protopanaxatriol are capable of binding to GR to activate its nuclear translocation, and to suppress the nuclear factor-kappa beta activity in GR-positive HeLa and HEK293 cells, but not in GR-low level COS-7 cells. Interestingly, no transactivation activity was observed, whereas suppression of the dexamethasone-induced transactivation of GR and induction of apoptosis in HeLa and HepG2 cells were observed. Thus, our results indicate that protopanaxadiol and protopanaxatriol could be considered as potent and selective GR agonist.
Culture and health Napier, A David, PhD; Ancarno, Clyde, PhD; Butler, Beverley, PhD ...
The Lancet (British edition),
11/2014, Letnik:
384, Številka:
9954
Journal Article
Recenzirano
Although culture can be considered as a set of subjective values that oppose scientific objectivity, we challenge this view in this Commission by claiming that all people have systems of value that ...are unexamined. Such systems are, at times, diffuse, and often taken for granted, but are always dynamic and changing. They produce novel and sometimes perplexing needs, to which established caregiving practices often adjust slowly.
Muscle loss during aging and disuse is a highly prevalent and disabling condition, but knowledge about cellular pathways mediating muscle atrophy is still limited. Given the postmitotic nature of ...skeletal myocytes, the maintenance of cellular homeostasis relies on the efficiency of cellular quality control mechanisms. In this scenario, alterations in mitochondrial function are considered a major factor underlying sarcopenia and muscle atrophy. Damaged mitochondria are not only less bioenergetically efficient, but also generate increased amounts of reactive oxygen species, interfere with cellular quality control mechanisms, and display a greater propensity to trigger apoptosis. Thus, mitochondria stand at the crossroad of signaling pathways that regulate skeletal myocyte function and viability. Studies on these pathways have sometimes provided unexpected and counterintuitive results, which suggests that they are organized into a complex, heterarchical network that is currently insufficiently understood. Untangling the complexity of such a network will likely provide clinicians with novel and highly effective therapeutics to counter the muscle loss associated with aging and disuse. In this review, we summarize the current knowledge on the mechanisms whereby mitochondrial dysfunction intervenes in the pathogenesis of sarcopenia and disuse atrophy, and highlight the prospect of targeting specific processes to treat these conditions.
Aging affects mitochondria in a tissue-specific manner. Calorie restriction (CR) is, so far, the only intervention able to delay or prevent the onset of several age-related changes also in ...mitochondria. Using livers from middle age (18-month-old), 28-month-old and 32-month-old ad libitum-fed and 28-month-old calorie-restricted rats we found an age-related decrease in mitochondrial DNA (mtDNA) content and mitochondrial transcription factor A (TFAM) amount, fully prevented by CR. We revealed also an age-related decrease, completely prevented by CR, for the proteins PGC-1α NRF-1 and cytochrome c oxidase subunit IV, supporting the efficiency of CR to forestall the age-related decrease in mitochondrial biogenesis. Furthermore, CR counteracted the age-related increase in oxidative damage to proteins, represented by the increased amount of oxidized peroxiredoxins (PRX-SO3) in the ad libitum-fed animals. An unexpected age-related decrease in the mitochondrial proteins peroxiredoxin III (Prx III) and superoxide dismutase 2 (SOD2), usually induced by increased ROS and involved in mitochondrial biogenesis, suggested a prevailing relevance of the age-reduced mitochondrial biogenesis above the induction by ROS in the regulation of expression of these genes with aging. The partial prevention of the decrease in Prx III and SOD2 proteins by CR also supported the preservation of mitochondrial biogenesis in the anti-aging action of CR. To investigate further the age- and CR-related effects on mitochondrial biogenesis we analyzed the in vivo binding of TFAM to specific mtDNA regions and demonstrated a marked increase in the TFAM-bound amounts of mtDNA at both origins of replication with aging, fully prevented by CR. A novel, positive correlation between the paired amounts of TFAM-bound mtDNA at these sub-regions was found in the joined middle age ad libitum-fed and 28-month-old calorie-restricted groups, but not in the 28-month-old ad libitum-fed counterpart suggesting a quite different modulation of TFAM binding at both origins of replication in aging and CR.
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Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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