Age-related alterations of skeletal muscle metabolism by intermittent hypoxia and trhanalogue treatment

Pastoris, Ornella; Dossena, Maurizia; Arnaboldi, R.; Gorini, A.; Villa, R. F.

doi:10.1016/1043-6618(94)80008-1

Cited by 9 publications

(10 citation statements)

References 36 publications

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“…This lack of effect of age on skeletal muscle AMPK is somewhat surprising in light of the literature showing that aging causes metabolic changes and ATP depletion that might be expected to activate AMPK (11). However, our data support the possibility that while the aged skeletal muscle may be depleted in high-energy phosphates, the factor that most directly regulates AMPK activity, the AMP-to-ATP ratio, remains normal (27). It is also possible that different skeletal muscles present different degrees of metabolic deterioration with aging.…”

Section: Discussioncontrasting

confidence: 54%

Effects of aging on cardiac and skeletal muscle AMPK activity: basal activity, allosteric activation, and response to in vivo hypoxemia in mice

González¹,

Kumar²,

Mulligan³

et al. 2004

American Journal of Physiology-Regulatory, Integrative and Comp

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. Effects of aging on cardiac and skeletal muscle AMPK activity: basal activity, allosteric activation, and response to in vivo hypoxemia in mice. Am J Physiol Regul Integr Comp Physiol 287: R1270 -R1275, 2004. First published July 29, 2004 doi:10.1152/ajpregu.00409.2004.-Although a diminished ability of tissues and organisms to tolerate stress is a clinically important hallmark of normal aging, little is known regarding its biochemical basis. Our goal was to determine whether age-associated changes in AMP-activated protein kinase (AMPK), a key regulator of cellular metabolism during the stress response, might contribute to the poor stress tolerance of aged cardiac and skeletal muscle. Basal AMPK activity and the degree of activation of AMPK by AMP and by in vivo hypoxemia (arterial PO2 of 39 mmHg) were measured in cardiac and skeletal muscle (gastrocnemius) from 5-and 24-mo-old C57Bl/6 mice. In the heart, neither basal AMPK activity nor its allosteric activation by AMP was affected by age. However, after 10 min of hypoxemia, the activity of ␣2-AMPK, but not ␣1-AMPK, was significantly higher in the hearts from old than from young mice (P Ͻ 0.005), this difference being due to differences in phosphorylation of ␣2-AMPK. Significant activation of AMPK in the young hearts did not occur until 30 min of hypoxemia (P Ͻ 0.01), stress that was poorly tolerated by the old mice (mortality ϭ 67%). In contrast, AMPK activity in gastrocnemius muscle was unaffected by age or hypoxemia. We conclude that the age-associated decline in hypoxic tolerance in cardiac and skeletal muscle is not caused by changes in basal AMPK activity or a blunted AMPK response to hypoxia. Activation of AMPK by in vivo hypoxia is slower and more modest than might be predicted from in vitro and ex vivo experiments.

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Section: Discussioncontrasting

confidence: 54%

Effects of aging on cardiac and skeletal muscle AMPK activity: basal activity, allosteric activation, and response to in vivo hypoxemia in mice

González¹,

Kumar²,

Mulligan³

et al. 2004

American Journal of Physiology-Regulatory, Integrative and Comp

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“…The metabolic changes observed in this study are similar in some aspects to the response of astroglia and non-neuronal mammalian tissues (e.g., muscle) to hypoxia (Semenza et al, 1996;Iyer, 1998), as well as CNS tissues of anoxia tolerant organisms (Hochachka and Lutz, 2001). For example, increased activities of HK and LDH have been reported during hypobaric hypoxia (400 mm Hg for 14 and 28 days) in guinea pig heart (Barrie and Harris, 1976) and severe intermittent hypoxia (8.5% oxygen, 12 hours/day for 4 weeks) in rat gastronemius muscle (Pastoris et al, 1994(Pastoris et al, , 1995. Similarly, exposure of mouse lung macrophage (LM) cells to hypoxia (pO 2 : 10-25 torr) for 96 hours led to increases in activities of glycolytic enzymes, including HK (⇑117%) and LDH (⇑151%) (Hance et al, 1980;Robin et al, 1984).…”

Section: Discussionmentioning

confidence: 99%

Effects of continuous hypoxia on energy metabolism in cultured cerebro-cortical neurons

et al. 2008

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Mechanisms underlying hypoxia-induced neuronal adaptation have not been fully elucidated. In the present study we investigated glucose metabolism and the activities of glycolytic and TCA cycle enzymes in cerebro-cortical neurons exposed to hypoxia (3 days in 1% of O 2 ) or normoxia (room air). Hypoxia led to increased activities of LDH (251%), PK (90%), and HK (24%) and decreased activities of CS (15%) and GDH (34%). Neurons were incubated with [1-13 C]glucose for 45 and 120 min under normoxic or hypoxic (120 min only) conditions and 13 C enrichment determined in the medium and cell extract using 1 H-{ 13 C}-NMR. In hypoxia-treated neurons [3-13 C]lactate release into the medium was 428% greater than in normoxia-treated controls (45-min normoxic incubation) and total flux through lactate was increased by 425%. In contrast glucose oxidation was reduced significantly in hypoxia-treated neurons, even when expressed relative to total cellular protein, which correlated with the reduced activities of the measured mitochondrial enzymes. The results suggest that surviving neurons adapt to prolonged hypoxia by up-regulation of glycolysis and downregulation of oxidative energy metabolism, similar to certain other cell types. The factors leading to adaptation and survival for some neurons but not others remains to be determined.

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“…Not only are there widely varying intermittent and chronic hypoxia paradigms and species but variables that have been demonstrated to influence enzyme activity were not factored in. These include days of exposure to either IH (44,74,75) or chronic hypoxia (79), the level of exercise conditioning during exposure (34,62,63), and age (73). Nevertheless, the relationship seems to suggest a biphasic pattern of response in which strategies promoting stimulation of oxidative capacity are reversed at a critical PO 2 .…”

Section: Metabolic Adaptationsmentioning

confidence: 99%

“…For example, intermittent bouts of exercise at altitude, as might occur during mountain climbing, may represent a superimposed IHlike stimulus on top of a chronic hypoxia stimulus. Furthermore, some of the models of long-cycle IH provide a hypoxic stimulus for as long as 12 h/day, which may approach a chronic hypoxic environment (73)(74)(75). Still other models of continuous altitude acclimatization are performed at altitudes low enough that it is likely muscles are exposed to significant hypoxia only during exercise (57,63).…”

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confidence: 99%

Invited Review: Adaptive responses of skeletal muscle to intermittent hypoxia: the known and the unknown

Clanton¹,

Klawitter

2001

Journal of Applied Physiology

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Intermittent hypoxia (IH) describes conditions of repeated, transient reductions in O2 that may trigger unique adaptations. Rest periods during IH may avoid potentially detrimental effects of long-term O2 deprivation. For skeletal muscle, IH can occur in conditions of obstructive sleep apnea, transient altitude exposures (with or without exercise), intermittent claudication, cardiopulmonary resuscitation, neonatal blood flow obstruction, and diving responses of marine animals. Although it is likely that adaptations in these conditions vary, some patterns emerge. Low levels of hypoxia shift metabolic enzyme activity toward greater aerobic poise; extreme hypoxia shifts metabolism toward greater anaerobic potential. Some conditions of IH may also inhibit lactate release during exercise. Many related cellular phenomena could be involved in the response, including activation of specific O2 sensors, reactive oxygen and nitrogen species, preconditioning, hypoxia-induced transcription factors, regulation of ion channels, and influences of paracrine/hormonal stimuli. The net effect of a variety of adaptive programs to IH may be to preserve contractile function and cell integrity in hypoxia or anoxia, a response that does not always translate into improvements in exercise performance.

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Age-related alterations of skeletal muscle metabolism by intermittent hypoxia and trhanalogue treatment

Cited by 9 publications

References 36 publications

Effects of aging on cardiac and skeletal muscle AMPK activity: basal activity, allosteric activation, and response to in vivo hypoxemia in mice

Effects of aging on cardiac and skeletal muscle AMPK activity: basal activity, allosteric activation, and response to in vivo hypoxemia in mice

Effects of continuous hypoxia on energy metabolism in cultured cerebro-cortical neurons

Invited Review: Adaptive responses of skeletal muscle to intermittent hypoxia: the known and the unknown

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