Hypoxia is increasingly recognized as an important physiological driving force.A specific transcriptional program,induced by a decrease in oxygen(O2)availability,for example,inspiratory hypoxia at high altitude,allows...Hypoxia is increasingly recognized as an important physiological driving force.A specific transcriptional program,induced by a decrease in oxygen(O2)availability,for example,inspiratory hypoxia at high altitude,allows cells to adapt to lower O2 and limited energy metabolism.This transcriptional program is partly controlled by and partly independent of hypoxia-inducible factors.Remarkably,this same transcriptional program is stimulated in the brain by extensive motor-cognitive exercise,leading to a relative decrease in O2 supply,compared to the acutely augmented O2 requirement.We have coined the term“functional hypoxia”for this important demand-responsive,relative reduction in O2 availability.Functional hypoxia seems to be critical for enduring adaptation to higher physiological challenge that includes substantial“brain hardware upgrade,”underlying advanced performance.Hypoxia-induced erythropoietin expression in the brain likely plays a decisive role in these processes,which can be imitated by recombinant human erythropoietin treatment.This article review presents hints of how inspiratory O2 manipulations can potentially contribute to enhanced brain function.It thereby provides the ground for exploiting moderate inspiratory plus functional hypoxia to treat individuals with brain disease.Finally,it sketches a planned multistep pilot study in healthy volunteers and first patients,about to start,aiming at improved performance upon motor-cognitive training under inspiratory hypoxia.展开更多
Hypoxia is more and more perceived as pivotal physiological driving force,allowing cells in the brain and elsewhere to acclimate to lowered oxygen(O_(2)),and abridged metabolism.The mediating transcription program is ...Hypoxia is more and more perceived as pivotal physiological driving force,allowing cells in the brain and elsewhere to acclimate to lowered oxygen(O_(2)),and abridged metabolism.The mediating transcription program is induced by inspiratory hypoxia but also by intensive motor-cognitive tasks,provoking a relative decrease in O_(2) in relation to the acutely augmented requirement.We termed this fundamental,demand-dependent drop in O_(2) availability"functional hypoxia."Major players in the hypoxia response are hypoxia-inducible factors(HIFs)and associated prolyl-hydroxylases.HIFs are transcription factors,stabilized by low O_(2) accessibility,and control expression of a multitude of genes.Changes in oxygen,however,can also be sensed via other pathways,among them the thiol-oxidase(2-aminoethanethiol)dioxygenase.Considering the far-reaching biological response to hypoxia,hitherto mostly observed in rodents,we initiated a translational project,combining mild to moderate inspiratory with functional hypoxia.We had identified this combination earlier to benefit motor-cognitive attainment in mice.A total of 20 subjects were included:13 healthy individuals and 7 patients with depression and/or autism spectrum disorder.Here,we show that motor-cognitive training under inspiratory hypoxia(12%O_(2))for 3.5 h daily over 3 weeks is optimally tolerated.We present first signals of beneficial effects on general well-being,cognitive performance,physical fitness and psychopathology.Erythropoietin in serum increases under hypoxia and flow cytometry analysis of blood reveals several immune cell types to be mildly modulated by hypoxia.To obtain reliable information regarding the"add-on"value of inspiratory on top of functional hypoxia,induced by motor-cognitive training,a single-blind study—with versus without inspiratory hypoxia—is essential and outlined here.展开更多
基金supported by the Max Planck Society,the Max Planck Förderstiftung,the Deutsche Forschungsgemeinschaft(DFG,German Research Foundation),via DFG-Center for Nanoscale Microscopy&Molecular Physiology of the Brain(CNMPB)and DFG-TRR 274/12020–408885537.
文摘Hypoxia is increasingly recognized as an important physiological driving force.A specific transcriptional program,induced by a decrease in oxygen(O2)availability,for example,inspiratory hypoxia at high altitude,allows cells to adapt to lower O2 and limited energy metabolism.This transcriptional program is partly controlled by and partly independent of hypoxia-inducible factors.Remarkably,this same transcriptional program is stimulated in the brain by extensive motor-cognitive exercise,leading to a relative decrease in O2 supply,compared to the acutely augmented O2 requirement.We have coined the term“functional hypoxia”for this important demand-responsive,relative reduction in O2 availability.Functional hypoxia seems to be critical for enduring adaptation to higher physiological challenge that includes substantial“brain hardware upgrade,”underlying advanced performance.Hypoxia-induced erythropoietin expression in the brain likely plays a decisive role in these processes,which can be imitated by recombinant human erythropoietin treatment.This article review presents hints of how inspiratory O2 manipulations can potentially contribute to enhanced brain function.It thereby provides the ground for exploiting moderate inspiratory plus functional hypoxia to treat individuals with brain disease.Finally,it sketches a planned multistep pilot study in healthy volunteers and first patients,about to start,aiming at improved performance upon motor-cognitive training under inspiratory hypoxia.
基金ERC Advanced Grant acronym BREPOCI,Grant/Award Number:101054369ALTIBRAIN,Grant/Award Number:101043416DFG,Grant/Award Number:TRR-274/12020-408885537。
文摘Hypoxia is more and more perceived as pivotal physiological driving force,allowing cells in the brain and elsewhere to acclimate to lowered oxygen(O_(2)),and abridged metabolism.The mediating transcription program is induced by inspiratory hypoxia but also by intensive motor-cognitive tasks,provoking a relative decrease in O_(2) in relation to the acutely augmented requirement.We termed this fundamental,demand-dependent drop in O_(2) availability"functional hypoxia."Major players in the hypoxia response are hypoxia-inducible factors(HIFs)and associated prolyl-hydroxylases.HIFs are transcription factors,stabilized by low O_(2) accessibility,and control expression of a multitude of genes.Changes in oxygen,however,can also be sensed via other pathways,among them the thiol-oxidase(2-aminoethanethiol)dioxygenase.Considering the far-reaching biological response to hypoxia,hitherto mostly observed in rodents,we initiated a translational project,combining mild to moderate inspiratory with functional hypoxia.We had identified this combination earlier to benefit motor-cognitive attainment in mice.A total of 20 subjects were included:13 healthy individuals and 7 patients with depression and/or autism spectrum disorder.Here,we show that motor-cognitive training under inspiratory hypoxia(12%O_(2))for 3.5 h daily over 3 weeks is optimally tolerated.We present first signals of beneficial effects on general well-being,cognitive performance,physical fitness and psychopathology.Erythropoietin in serum increases under hypoxia and flow cytometry analysis of blood reveals several immune cell types to be mildly modulated by hypoxia.To obtain reliable information regarding the"add-on"value of inspiratory on top of functional hypoxia,induced by motor-cognitive training,a single-blind study—with versus without inspiratory hypoxia—is essential and outlined here.
