Muscle lipofuscin content and satellite cell volume is increased after high altitude exposure in humans

Martinelli, M; Winterhalder, Ralph; Cerretelli, Paolo; Howald, H.; Hoppeler, Hans

doi:10.1007/bf01939930

Cited by 62 publications

(56 citation statements)

References 23 publications

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“…We found the volume fraction of lipofuscin inclusions ( Fig. 2) to be significantly increased by over 2-fold after return from the expeditions (Martinelli et al 1990). Lipofuscin is believed to be a degradation product of mitochondria, prevailing under conditions of increased oxygen radical formation (Brunk & Terman, 2002).…”

Section: Long-term Hypoxia On Mountaineering Expeditionsmentioning

confidence: 76%

“…Moreover, ROS-activated signalling events involving MAPK and PI-3 K/Akt have been implied in the modulation of the transcriptional activity of HIF-1a (Richard et al 1999;Minet et al 2001). Last but not least, ROS production potentially could explain the accumulation of the by-products of radical metabolism, such as the breakdown product of mitochondria, lipofuscin (Brunk & Terman, 2002), in low-landers after having spent weeks at high altitude (Martinelli et al 1990). …”

Section: Ros Production During Hypoxia: Are Mitochondria Oxygen Sensors?mentioning

confidence: 99%

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Response of Skeletal Muscle Mitochondria to Hypoxia

Hoppeler

Vogt

Weibel

et al. 2003

Experimental Physiology

262

203

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This review explores the current concepts relating the structural and functional modifications of skeletal muscle mitochondria to the molecular mechanisms activated when organisms are exposed to a hypoxic environment. In contrast to earlier assumptions it is now established that permanent or long-term exposure to severe environmental hypoxia decreases the mitochondrial content of muscle fibres. Oxidative muscle metabolism is shifted towards a higher reliance on carbohydrates as a fuel, and intramyocellular lipid substrate stores are reduced. Moreover, in muscle cells of mountaineers returning from the Himalayas, we find accumulations of lipofuscin, believed to be a mitochondrial degradation product. Low mitochondrial contents are also observed in high-altitude natives such as Sherpas. In these subjects high-altitude performance seems to be improved by better coupling between ATP demand and supply pathways as well as better metabolite homeostasis. The hypoxia-inducible factor 1 (HIF-1) has been identified as a master regulator for the expression of genes involved in the hypoxia response, such as genes coding for glucose transporters, glycolytic enzymes and vascular endothelial growth factor (VEGF). HIF-1 achieves this by binding to hypoxia response elements in the promoter regions of these genes, whereby the increase of HIF-1 in hypoxia is the consequence of a reduced degradation of its dominant subunit HIF-1a. A further mechanism that seems implicated in the hypoxia response of muscle mitochondria is related to the formation of reactive oxygen species (ROS) in mitochondria during oxidative phosphorylation. How exactly ROS interfere with HIF-1a as well as MAP kinase and other signalling pathways is debated. The current evidence suggests that mitochondria themselves could be important players in oxygen sensing.

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Section: Long-term Hypoxia On Mountaineering Expeditionsmentioning

confidence: 76%

Section: Ros Production During Hypoxia: Are Mitochondria Oxygen Sensors?mentioning

confidence: 99%

Response of Skeletal Muscle Mitochondria to Hypoxia

Hoppeler

Vogt

Weibel

et al. 2003

Experimental Physiology

262

203

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“…Two studies have reported cumulative oxidative stress and damage in resting muscle of healthy subjects exposed to an oxygen deficient environment. Martinelli and co-workers 12 reported a threefold increase in basal levels of lipofuscin, a pigment marker of cumulative oxidative stress, in the vastus lateralis of climbers after a high altitude expedition over 5000 m for 8 weeks. More recently, Lundby and colleagues 13 reported an increase in resting muscle oxidative DNA damage in seven healthy subjects after 2 weeks at 4100 m. Chronic hypoxaemia, a common physiopathological consequence of COPD, is associated with poor tolerance of peripheral muscle exercise.…”

mentioning

confidence: 99%

Hypoxaemia enhances peripheral muscle oxidative stress in chronic obstructive pulmonary disease

Koechlin

Maltais²,

Saey³

et al. 2005

Thorax

120

108

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Background: Because oxidative stress affects muscle function, the underlying mechanism to explain exercise induced peripheral muscle oxidative stress in patients with chronic obstructive pulmonary disease (COPD) is clinically relevant. This study investigated whether chronic hypoxaemia in COPD worsens peripheral muscle oxidative stress and whether an abnormal muscle inflammatory process is associated with it. Methods: Nine chronically hypoxaemic and nine non-hypoxaemic patients performed repeated knee extensions until exhaustion. Biopsy specimens were taken from the vastus lateralis muscle before and 48 hours after exercise. Muscle oxidative stress was evaluated by lipid peroxidation (lipofuscin and thiobarbituric acid reactive substances (TBARs)) and oxidised proteins. Inflammation was evaluated by quantifying muscle neutrophil and tumour necrosis factor (TNF)-a levels. Results: When both groups were taken together, arterial oxygen pressure was positively correlated with quadriceps endurance time (n = 18, r = 0.57; p,0.05). At rest, quadriceps lipofuscin inclusions were significantly greater in hypoxaemic patients than in non-hypoxaemic patients (2.9 (0.2) v 2.0 (0.3) inclusions/fibre; p,0.05). Exercise induced a greater increase in muscle TBARs and oxidised proteins in hypoxaemic patients than in non-hypoxaemic patients (40.6 (9.1)% v 10.1 (5.8)% and 51.2 (11.9)% v 3.7 (12.2)%, respectively, both p = 0.01). Neutrophil levels were significantly higher in hypoxaemic patients than in non-hypoxaemic patients (53.1 (11.6) v 21.5 (11.2) counts per fibre 6 10 23 ; p,0.05). Exercise did not alter muscle neutrophil levels in either group. Muscle TNF-a was not detected at baseline or after exercise. Conclusion: Chronic hypoxaemia was associated with lower quadriceps endurance time and worsened muscle oxidative stress at rest and after exercise. Increased muscle neutrophil levels could be a source of the increased baseline oxidative damage. The involvement of a muscle inflammatory process in the exercise induced oxidative stress of patients with COPD remains to be shown.

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“…Mitochondria play a central role in all these processes due to their active implication in energy production and the regulation of cell death. This is supported by the selective accumulation of the mitochondrial breakdown product lipofuscin concomitantly with reduced mitochondrial volume density in Caucasian mountaineers after altitude exposure (Martinelli et al, 1990;Gelfi et al, 2004). These alterations resemble mitochondrial autophagy, which removes damaged mitochondria and serves to control muscle fiber atrophy that originates from local fiber death induced by cytochome c release from injured mitochondria (Decker and Wildenthal, 1980;Terman et al, 2004;Gustafsson and Gottlieb, 2008).…”

Section: Zones Of Adaptation To Exercise In Hypoxiamentioning

confidence: 98%

Plasticity of the Muscle Proteome to Exercise at Altitude

Flueck

2009

High Altitude Medicine & Biology

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The ascent of humans to the summits of the highest peaks on Earth initiated a spurt of explorations into the physiological consequences of physical activity at altitude. The past three decades have demonstrated that the resetting of respiratory and cardiovascular control with chronic exposure to altitudes above 4000 m is accompanied by important structural-functional adjustments of skeletal muscle. The fully altitude-adapted phenotype preserves energy charge at reduced aerobic capacity through the promotion of anaerobic substrate flux and tighter metabolic control, often at the expense of muscle mass. In seeming contrast, intense physical activity at moderate hypoxia (2500 to 4000 m) modifies this response in both low and high altitude natives through metabolic compensation by elevating local aerobic capacity and possibly preventing muscle fiber atrophy. The combined use of classical morphometry and contemporary proteomic technology provides a highly resolved picture of the temporal control of hypoxiainduced muscular adaptations. The muscle proteome signature identifies mitochondrial autophagy and protein degradation as prime adaptive mechanisms to passive altitude exposure and ascent to extreme altitude. Protein measures also explain the lactate paradox by a sparing of glycolytic enzymes from general muscle wasting. Enhanced mitochondrial and angiogenic protein expression in human muscle with exercise up to 4000 m is related to the reduction in intramuscular oxygen content below 1% (8 torr), when the master regulator of hypoxia-dependent gene expression, HIF-1alpha, is stabilized. Accordingly, it is proposed here that the catabolic consequences of chronic hypoxia exposure reflect the insufficient activation of hypoxia-sensitive signaling and the suppression of energy-consuming protein translation. The ascent of humans to the summits of the highest peaks on Earth initiated a spurt of explorations into the physiological consequences of physical activity at altitude. The past three decades have demonstrated that the resetting of respiratory and cardiovascular control with chronic exposure to altitudes above 4000 m is accompanied by important structural-functional adjustments of skeletal muscle. The fully altitude-adapted phenotype preserves energy charge at reduced aerobic capacity through the promotion of anaerobic substrate flux and tighter metabolic control, often at the expense of muscle mass. In seeming contrast, intense physical activity at moderate hypoxia (2500 to 4000 m) modifies this response in both low and high altitude natives through metabolic compensation by elevating local aerobic capacity and possibly preventing muscle fiber atrophy. The combined use of classical morphometry and contemporary proteomic technology provides a highly resolved picture of the temporal control of hypoxia-induced muscular adaptations. The muscle proteome signature identifies mitochondrial autophagy and protein degradation as prime adaptive mechanisms to passive altitude exposure and ascent to extreme altitude. P...

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Muscle lipofuscin content and satellite cell volume is increased after high altitude exposure in humans

Cited by 62 publications

References 23 publications

Response of Skeletal Muscle Mitochondria to Hypoxia

Response of Skeletal Muscle Mitochondria to Hypoxia

Hypoxaemia enhances peripheral muscle oxidative stress in chronic obstructive pulmonary disease

Plasticity of the Muscle Proteome to Exercise at Altitude

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