II. Morphological Adaptations of Human Skeletal Muscle to Chronic Hypoxia*

Hoppeler, Hans; Kleinert, Edward L.; Schlegel, Christoph; Claassen, Horst; Howald, H.; Kayar, Susan R.; Cerretelli, P.

doi:10.1055/s-2007-1024846

Cited by 258 publications

(240 citation statements)

References 16 publications

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“…For the high-altitude dwellers such as Tibetans and Quechuas who have been living at Ն3,500 m for thousands of generations, the capillary density in skeletal muscle is within the normal range and the mitochondrial content of skeletal muscle is also close to that of the lowland population, yet they develop muscle fibers with smaller cross-sectional areas (29). Prolonged exposure to high-altitude hypoxia (24) or simulated hypoxia in a chamber (33) can also cause a reduction of muscle fiber size and loss of skeletal muscle mass, despite a decrease in the perfusion area per capillary (24). These observations strongly suggest that the decrease in skeletal muscle mass and myofiber size directly results from hypoxia.…”

Section: Discussionmentioning

confidence: 99%

Adaptive Myogenesis under Hypoxia

Yun

Lin

Giaccia

2005

Molecular and Cellular Biology

126

171

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Previous studies have indicated that myoblasts can differentiate and repair muscle injury after an ischemic insult. However, it is unclear how hypoxia or glucose deprivation in the ischemic microenvironment affects myoblast differentiation. We have found that myogenesis can adapt to hypoxic conditions. This adaptive mechanism is accompanied by initial inhibition of the myoD, E2A, and myogenin genes followed by resumption of their expression in an oxygen-dependent manner. The regulation of myoD transcription by hypoxia is correlated with transient deacetylation of histones associated with the myoD promoter. It is noteworthy that, unlike the differentiation of other cell types such as preadipocytes or chondroblasts, the effect of hypoxia on myogenesis is independent of HIF-1, a ubiquitous regulator of transcription under hypoxia. While myogenesis can also adapt to glucose deprivation, the combination of severe hypoxia and glucose deprivation found in an ischemic environment results in pronounced loss of myoblasts. Our studies indicate that the ischemic muscle can be repaired via the adaptive differentiation of myogenic precursors, which depends on the levels of oxygen and glucose in the ischemic microenvironment.Skeletal muscle possesses the remarkable ability to withstand chronic ischemia. However, the newly developed muscle fibers tend to be smaller in diameter than those of healthy, nonischemic myofibers (46). Interestingly, chronic exposure to high altitude can also result in smaller myofiber area and lower muscle mass in mountaineers (25). Similar myofiber differences are also observed in healthy people who live at high altitude for generations (25). Taken together, these observations suggest that decreased oxygen tension or hypoxia alone may be sufficient to alter the differentiation of myoblasts.Ischemic muscle damage is repaired by myogenic satellite cells, a small population of precursor cells located between myofibers (12,23,47). When stimulated, the otherwise quiescent satellite cells undergo terminal differentiation into myocytes to regenerate damaged myofibers. It has been found that cultured satellite cells form new muscle fibers when transplanted into ischemic muscle (12). The myogenic differentiation of myoblasts is highly orchestrated by a family of myogenic regulatory factors (MRFs), such as myoD, myogenin, myf5, and MRF4 in collaboration with the E2A gene products (E12 or E47) and/or the myogenic enhancing factors (6, 41, 53). Although a plethora of information on the embryonic development of muscle exists, there is still a lack of clear understanding of how postnatal myogenic satellite cells are regulated during muscle regeneration, especially by their microenvironment.Tissue ischemia in myocardium and skeletal muscle results in hypoxia and elevates the expression of the hypoxia-inducible transcription factor HIF-1␣ and its downstream gene, VEGF (32,40). Although ischemic tissue is exposed to hypoxia and decreased nutritional supply, cells will alter their metabolism, proliferation, and differe...

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Section: Discussionmentioning

confidence: 99%

Adaptive Myogenesis under Hypoxia

Yun

Lin

Giaccia

2005

Molecular and Cellular Biology

126

171

View full text Add to dashboard Cite

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“…Hypoxia can be caused by a generalized reduction in oxygen delivery, such as altitude and pulmonary diseases, or by disruption in the local blood supply, such as an ischemic disorder. It is known that chronic exposure to high-altitude hypoxia (Hoppeler et al, 1990;Howald and Hoppeler, 2003;MacDougall et al, 1991) can cause a reduction of muscle fibre size and loss of skeletal muscle mass in mountaineers. Similar findings have been reported in healthy people who live at high altitude for generations and in rats chronically exposed to a simulated hypobaric altitude (Sillau and Banchero, 1977).…”

Section: Version Postprintmentioning

confidence: 99%

Myostatin up-regulation is associated with the skeletal muscle response to hypoxic stimuli

Hayot

Rodriguez

Vernus

et al. 2011

Molecular and Cellular Endocrinology

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Myostatin up-regulation is associated with the skeletal muscle response to hypoxic stimuli, Molecular and Cellular Endocrinology (2010), doi:10.1016/j.mce.2010 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Version postprintComment citer ce document : Hayot, M., Rodriguez, J., Vernus, B., Carnac, G., Jean, E., Allen, D., Goret, L., Obert, P., Candau, R., A c c e p t e d M a n u s c r i p t 2 ABSTRACTMyostatin and hypoxia signalling pathways are able to induce skeletal muscle atrophy, but whether a relationship between these two pathways exists is currently unknown. Here, we tested the hypothesis that a potential mechanism for hypoxia effect on skeletal muscle may be through regulation of myostatin. We reported an induction of myostatin expression in muscles of rats exposed to chronic hypoxia. Interestingly, we also demonstrated increased skeletal muscle myostatin protein expression in skeletal muscle of hypoxemic patients with severe Keywords : hypoxic stimulus, myostatin, skeletal muscle atrophy, COPD, myotubes Version postprintComment citer ce document : Hayot, M., Rodriguez, J., Vernus, B., Carnac, G., Jean, E., Allen, D., Goret, L., Obert, P., Candau, R., Bonnieu, A. (2011). Myostatin up-regulation is associated with the skeletal muscle response to hypoxic stimuli.

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“…Our finding is also contrary to the classic expectations for muscle structure adjustments based on constraints associated with apneustic or hypoxic exercise. Hypoxic tissue environments, similar to the chronic hypoxia of mountaineering, are generally associated with CSA declines to improve tissue oxygen handling (Hoppeler et al, 1990). The regular apneustic exercise in diving, air breathing vertebrates should result in chronic submergence hypoxia (Guyton et al, 1985;Qvist et al, 1986;Davis and Kanatous, 1999;Ponganis et al, 2007).…”

Section: Muscle Morphologymentioning

confidence: 99%

Diving into old age: muscular senescence in a large-bodied, long-lived mammal, the Weddell seal (Leptonychotes weddellii)

Hindle

Horning

Mellish

et al. 2009

Journal of Experimental Biology

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SUMMARYClassic aging theory postulates the absence of pronounced organismal senescence in wild animals since mortality probably occurs first. Large-bodied, long-lived mammals are a recognized exception to this tenet, yet organismal senescence has not been investigated to date in such mammals in the wild. Furthermore, oxidative stress theory of aging supports the suggestion that exercise hypoxia, as regularly incurred during apneustic foraging in diving mammals might lead to cellular dysfunction and accelerated aging. To determine if an aspect of organismal senescence occurs in wild marine mammals, we examined the pattern of skeletal muscle aging (contractile and connective tissue components of longissimus dorsi and pectoralis muscles) in freeranging adult Weddell seals (9-26 years). The average myocyte cross-sectional area was 22% greater with age in the longissiums dorsi, but no significant increase occurred in the pectoralis. Cross-sectional area was not related to body mass. Changes in myocyte number per area were consistent with the 35-40% age-increase in extracellular space in both muscle groups. Also consistent with extracellular space remodeling, total and relative collagen contents were significantly elevated in older seals (115% in longissimus dorsi; 65% in pectoralis). The ratio of muscle myocyte to collagen declined with age (50-63%) at both sites. Additionally, a shift towards a higher ratio of type I to type III collagen occurred with advancing age in both muscle groups (79% increase in pectoralis; 49% in longissimus dorsi). We reject the classic tenet and null-hypothesis that Weddell seals do not survive to an age where muscular senescence becomes detectable.

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II. Morphological Adaptations of Human Skeletal Muscle to Chronic Hypoxia*

Cited by 258 publications

References 16 publications

Adaptive Myogenesis under Hypoxia

Adaptive Myogenesis under Hypoxia

Myostatin up-regulation is associated with the skeletal muscle response to hypoxic stimuli

Diving into old age: muscular senescence in a large-bodied, long-lived mammal, the Weddell seal (Leptonychotes weddellii)

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