Publikasjoner
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Wohlwend, Martin; Laurila, Pirkka-Pekka; Williams, Kristine; Romani, Mario; Lima, Tanes & Pattawaran, Pattamaprapanont
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(2021).
The exercise-induced long noncoding RNA CYTOR promotes fast-twitch myogenesis in aging.
Science Translational Medicine.
ISSN 1946-6234.
13(623).
doi:
10.1126/scitranslmed.abc7367.
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Skeletal muscle displays remarkable plasticity upon exercise and is also one of the organs most affected by aging. Despite robust evidence that aging is associated with loss of fast-twitch (type II) muscle fibers, the underlying mechanisms remain to be elucidated. Here, we identified an exercise-induced long noncoding RNA, CYTOR, whose exercise responsiveness was conserved in human and rodents. Cytor overexpression in mouse myogenic progenitor cells enhanced myogenic differentiation by promoting fast-twitch cell fate, whereas Cytor knockdown deteriorated expression of mature type II myotubes. Skeletal muscle Cytor expression was reduced upon mouse aging, and Cytor expression in young mice was required to maintain proper muscle morphology and function. In aged mice, rescuing endogenous Cytor expression using adeno-associated virus serotype 9 delivery of CRISPRa reversed the age-related decrease in type II fibers and improved muscle mass and function. In humans, CYTOR expression correlated with type II isoform expression and was decreased in aged myoblasts. Increased CYTOR expression, mediated by a causal cis–expression quantitative trait locus located within a CYTOR skeletal muscle enhancer element, was associated with improved 6-min walk performance in aged individuals from the Helsinki Birth Cohort Study. Direct CYTOR overexpression using CRISPRa in aged human donor myoblasts enhanced expression of type II myosin isoforms. Mechanistically, Cytor reduced chromatin accessibility and occupancy at binding motifs of the transcription factor Tead1 by binding, and hence sequestering, Tead1. In conclusion, the long noncoding RNA Cytor was found to be a regulator of fast-twitch myogenesis in aging.
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Souza, Rodrigo W. A.; Alves, Christiano R. R.; Medeiros, Alessandra; Rolim, Natale Pinheiro Lage; Silva, Gustavo Jose Justo & Moreira, Jose Bianco Nascimento
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(2018).
Differential regulation of cysteine oxidative post-translational modifications in high and low aerobic capacity.
Scientific Reports.
8(1).
doi:
10.1038/s41598-018-35728-2.
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Given the association between high aerobic capacity and the prevention of metabolic diseases, elucidating the mechanisms by which high aerobic capacity regulates whole-body metabolic homeostasis is a major research challenge. Oxidative post-translational modifications (Ox-PTMs) of proteins can regulate cellular homeostasis in skeletal and cardiac muscles, but the relationship between Ox-PTMs and intrinsic components of oxidative energy metabolism is still unclear. Here, we evaluated the Ox-PTM profile in cardiac and skeletal muscles of rats bred for low (LCR) and high (HCR) intrinsic aerobic capacity. Redox proteomics screening revealed different cysteine (Cys) Ox-PTM profile between HCR and LCR rats. HCR showed a higher number of oxidized Cys residues in skeletal muscle compared to LCR, while the opposite was observed in the heart. Most proteins with differentially oxidized Cys residues in the skeletal muscle are important regulators of oxidative metabolism. The most oxidized protein in the skeletal muscle of HCR rats was malate dehydrogenase (MDH1). HCR showed higher MDH1 activity compared to LCR in skeletal, but not cardiac muscle. These novel findings indicate a clear association between Cys Ox-PTMs and aerobic capacity, leading to novel insights into the role of Ox-PTMs as an essential signal to maintain metabolic homeostasis.
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Smenes, Benedikte; Bækkerud, Fredrik Hjulstad; Slagsvold, Katrine Hordnes; Hassel, Erlend; Wohlwend, Martin & Pinho, Maria
[Vis alle 10 forfattere av denne artikkelen]
(2018).
Acute exercise is not cardioprotective and may induce apoptotic signalling in heart surgery: a randomized controlled trial.
Interactive Cardiovascular and Thoracic Surgery.
ISSN 1569-9293.
27(1),
s. 95–101.
doi:
10.1093/icvts/ivx439.
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OBJECTIVES During open-heart surgery, the myocardium experiences ischaemia–reperfusion injury. A single bout of moderate, 30-min exercise induces preconditioning and protects the heart from ischaemia–reperfusion injury in rats, but this has never been investigated in humans. We aimed to investigate whether 1 bout of moderate exercise 24 h prior to surgery protects against mitochondrial and cardiac damage. METHODS Patients scheduled for elective coronary artery bypass were eligible for this pilot study. Twenty were included and randomized to the treadmill exercise group (the EX group, n = 10) 24 h preoperatively or to standard presurgical procedures (control n = 10). Right atrial (RA) and left ventricular (LV) biopsies were collected immediately before and as long as possible after aortic cross-clamping to assess the primary outcome of mitochondrial respiration by respirometry, in addition to reactive oxygen species production by fluorometry and apoptotic transcripts. Cardiac troponin T and creatine kinase myocardial brain were measured in plasma at arrival, before surgery and 6 and 24 h postoperatively. RESULTS Mitochondrial respiration was lower in the EX group after surgery in the LV (Complex I −22%, P < 0.05 and maximal −23%, P < 0.05) and the right atrium (Complex I −25%, P < 0.05). Transcript level of the apoptosis-related marker caspase 3 was increased 1.5-fold in the LV prior to surgery in the EX group when compared with the control group, P < 0.05. Cardiac troponin T was 45% higher in the EX group than in the control group 6 h postoperatively (P = 0.03), although not significant when corrected for aortic cross-clamping time. CONCLUSIONS Results indicate that exercise did not precondition the heart against surgery-related damage. Exercise may render the myocardium and mitochondria more vulnerable to perioperative damage.
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Wohlwend, Martin Rainer; Olsen, Alexander; Håberg, Asta & Palmer, Helen
(2017).
Exercise Intensity-Dependent Effects on Cognitive Control Function during and after Acute Treadmill Running in Young Healthy Adults.
Frontiers in Psychology.
8.
doi:
10.3389/fpsyg.2017.00406.
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The idea that physical activity differentially impacts upon performance of various
cognitive tasks has recently gained increased interest. However, our current knowledge
about how cognition is altered by acute physical activity is incomplete. To measure how
different intensity levels of physical activity affect cognition during and after 1 bout of
physical activity, 30 healthy, young participants were randomized to perform a not-X
continuous performance test (CPT) during low (LI)- and moderate intensity (MI) running.
The same participants were subsequently randomized to perform the not-X CPT post
LI, MI, and high intensity (HI) running. In addition, exercise related mood changes were
assessed through a self-report measure pre and post running at LI, MI, and HI. Results
showed worsening of performance accuracy on the not-X CPT during one bout of
moderate compared to low intensity running. Post running, there was a linear decrease
in reaction time with increasing running intensity and no change in accuracy or mood.
The decreased reaction times post HI running recovered back to baseline within 20 min.
We conclude that accuracy is acutely deteriorated during the most straining physical
activity while a transient intensity-dependent enhancement of cognitive control function
is present following physical activity.
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Schaardenburgh, Michel van; Wohlwend, Martin Rainer; Rognmo, Øivind & Mattsson, Erney
(2017).
Calf raise exercise increases walking performance in patients with intermittent claudication.
Journal of Vascular Surgery.
ISSN 0741-5214.
65(5),
s. 1473–1482.
doi:
10.1016/j.jvs.2016.12.106.
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BACKGROUND: Symptoms of intermittent claudication (IC) are improved by exercise. The improvement might be secondary to increased blood perfusion or increased muscle mitochondrial capacity. Ischemia followed by reperfusion, also named preconditioning, is known to stimulate the mitochondria. We focused on a calf raise exercise inducing preconditioning in the calf muscle of patients with IC. We hypothesized that 8 weeks of this exercise would increase walking performance and mitochondrial capacity without a change in blood flow. METHODS: Patients with IC were randomized to either a calf raise exercise group (n = 14) or a traditional walking exercise group (n = 15). The calf raise group was instructed to perform a specific type of calf raise exercise three times a day. The walking group was instructed to walk near the pain threshold at least 30 minutes three times a week. Both interventions lasted 8 weeks and were not supervised. Measurements of walking performance, mitochondrial capacity, peak oxygen uptake, peripheral hemodynamics, and health-related quality of life were obtained on each patient before and after the intervention period. Adherence was measured by a training diary, and an activity monitor was used. RESULTS: The calf raise group improved pain-free walking distance by 44 meters (P = .04) and maximal walking distance by 99 meters (P = .047). Furthermore, claudication onset time increased by 123 seconds (P = .02), and peak walking time increased by 104 seconds (P = .01). The calf raise group increased the enzyme citrate synthase activity, which is a biomarker of mitochondrial volume-density in the muscle tissue (P = .02). The walking group did not increase any of these variables. Maximal blood flow, peak oxygen uptake, and mitochondrial respiration did not change in any group. The calf raise group experienced less disease anxiety (P < .01). Adherence to the instruction of exercise was 100% in the calf raise group and 80% in the walking group. The calf raise group maintained physical activity. A reduction in activity (P < .01) was found in the walking group. CONCLUSIONS: Calf raise exercise improves walking performance and increases mitochondrial volume-density in the gastrocnemius muscle without increasing blood flow in patients with IC.
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Schaardenburgh, Michel van; Wohlwend, Martin Rainer; Rognmo, Øivind & Mattsson, Erney
(2017).
Exercise in claudicants increase or
decrease walking ability and the response
relates to mitochondrial function.
Journal of Translational Medicine.
15(130).
doi:
10.1186/s12967-017-1232-6.
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Background Exercise of patients with intermittent claudication improves walking performance. Exercise does not usually increase blood flow, but seems to increase muscle mitochondrial enzyme activities. Although exercise is beneficial in most patients, it might be harmful in some. The mitochondrial response to exercise might therefore differ between patients. Our hypothesis was that changes in walking performance relate to changes in mitochondrial function after 8 weeks of exercise. At a subgroup level, negative responders decrease and positive responders increase mitochondrial capacity. Methods Two types of exercise were studied, calf raising and walking (n = 28). We wanted to see whether there were negative and positive responders, independent of type of exercise. Measurements of walking performance, peripheral hemodynamics, mitochondrial respiration and content (citrate synthase activity) were obtained on each patient before and after the intervention period. Multiple linear regression was used to test whether changes in peak walking time relate to mitochondrial function. Subgroups of negative (n = 8) and positive responders (n = 8) were defined as those that either decreased or increased peak walking time following exercise. Paired t test and analysis of covariance was used to test changes within and between subgroups. Results Changes in peak walking time were related to changes in mitochondrial respiration supported by electron transferring flavoprotein (ETF + CI)P (p = 0.004), complex I (CI + ETF)P (p = 0.003), complex I + complex II (CI + CII + ETF)P (p = 0.037) and OXPHOS coupling efficiency (p = 0.046) in the whole group. Negative responders had more advanced peripheral arterial disease. Mitochondrial respiration supported by electron transferring flavoprotein (ETF + CI)P (p = 0.0013), complex I (CI + ETF)P (p = 0.0005), complex I + complex II (CI + CII + ETF)P (p = 0.011) and electron transfer system capacity (CI + CII + ETF)E (p = 0.021) and OXPHOS coupling efficiency decreased in negative responders (p = 0.0007) after exercise. Positive responders increased citrate synthase activity (p = 0.010). Conclusions Changes in walking performance seem to relate to changes in mitochondrial function after exercise. Negative responders have more advanced peripheral arterial disease and decrease, while positive responders increase mitochondrial capacity.
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Moreira, Jose Bianco Nascimento; Wohlwend, Martin; Åmellem, Ingrid & Jannig, Paulo R.
(2016).
Age-dependent effects of bed rest in human skeletal muscle: Exercise to the rescue.
Journal of Physiology.
ISSN 0022-3751.
594(2),
s. 265–266.
doi:
10.1113/JP271758.
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Schaardenburgh, Michel van; Wohlwend, Martin Rainer; Rognmo, Øivind & Mattsson, Erney
(2016).
Mitochondrial respiration after one session of calf raise exercise in patients with peripheral vascular disease and healthy older adults.
PLOS ONE.
11:e0165038(10).
doi:
10.1371/journal.pone.0165038.
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Purpose: Mitochondria are essential for energy production in the muscle cell and for this they are dependent upon a sufficient supply of oxygen by the circulation. Exercise training has shown to be a potent stimulus for physiological adaptations and mitochondria play a central role. Whether changes in mitochondrial respiration are seen after exercise in patients with a reduced circulation is unknown. The aim of the study was to evaluate the time course and whether one session of calf raise exercise stimulates mitochondrial respiration in the calf muscle of patients with peripheral vascular disease. Methods: One group of patients with peripheral vascular disease (n = 11) and one group of healthy older adults (n = 11) were included. Patients performed one session of continuous calf raises followed by 5 extra repetitions after initiation of pain. Healthy older adults performed 100 continuous calf raises. Gastrocnemius muscle biopsies were collected at baseline and 15 minutes, one hour, three hours and 24 hours after one session of calf raise exercise. A multi substrate (octanoylcarnitine, malate, adp, glutamate, succinate, FCCP, rotenone) approach was used to analyze mitochondrial respiration in permeabilized fibers. Mixed-linear model for repeated measures was used for statistical analyses. Results: Patients with peripheral vascular disease have a lower baseline respiration supported by complex I and they increase respiration supported by complex II at one hour post-exercise. Healthy older adults increase respiration supported by electron transfer flavoprotein and complex I at one hour and 24 hours post-exercise. Conclusion:Our results indicate a shift towards mitochondrial respiration supported by complex II as being a pathophysiological component of peripheral vascular disease. Furthermore exercise stimulates mitochondrial respiration already after one session of calf raise exercise in patients with peripheral vascular disease and healthy older adults.
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Moreira, Jose Bianco Nascimento; Wohlwend, Martin; Alves, Marcia Netto Magalhaes; Wisløff, Ulrik & Bye, Anja
(2015).
A small molecule activator of AKT does not reduce ischemic injury of the rat heart.
Journal of Translational Medicine.
13(1).
doi:
10.1186/s12967-015-0444-x.
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Background Activation of protein kinase AKT is required for cardioprotection by ischemic preconditioning, and transgenic overexpression of AKT protects the heart against ischemia. However, it is unknown whether acute pharmacological activation of AKT alone, using a therapeutically relevant strategy, induces cardioprotection. In this study we provide the first evidence to clarify this question. Methods We used a recently described specific activator of AKT, the small molecule SC79, to treat rat hearts submitted to ischemia and reperfusion. Initially, isolated rat hearts were perfused with increasing doses of SC79 to verify the magnitude of AKT activation. Low and high doses were determined and used to treat hearts submitted to ischemia (35 minutes) and reperfusion (60 minutes), in a randomized and blinded design. AKT activation was verified by western immunobloting. Metabolic profile was determined by cardiac ATP content and mitochondrial enzyme activity, while cytosolic levels of cytochrome C and caspase-3 activity were used as markers of apoptosis. Ischemic injury was assessed by quantification of infarct size and cardiac release of creatine kinase and lactate dehydrogenase. Results SC79 activated cardiac AKT within 30 minutes in a dose-dependent fashion. ATP content was largely reduced by ischemia, but was not rescued by SC79. Similarly, mitochondrial enzyme activity was not affected by SC79. SC79 administered before ischemia or at reperfusion did not prevent cytosolic accumulation of cytochrome C and overactivation of caspase-3. Finally, SC79 failed to reduce infarct size or release of cardiac injury biomarkers at reperfusion. Conclusion We conclude that selective AKT activation by the synthetic molecule SC79 does not protect the rat heart against ischemic injury, indicating that acute pharmacological activation of AKT is not sufficient for cardioprotection.
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Schaardenburgh, Michel van; Wohlwend, Martin; Rognmo, Øivind & Mattsson, Erney
(2017).
Patients with intermittent claudication decrease or increase walking performance after an exercise intervention and this response relates to mitochondrial function.
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Wohlwend, Martin Rainer; Wisløff, Ulrik; Nes, Bjarne & Nauman, Javaid
(2017).
Personal Activity Intelligence (PAI) for promotion of physical activity and prevention of CVD.
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Schaardenburgh, Michel van; Wohlwend, Martin; Rognmo, Øivind & Mattsson, Erney
(2017).
Training Of Claudicants Can Also Be Harmful.
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Wohlwend, Martin Rainer; Chawla, Konika; Wisløff, Ulrik & Moreira, Jose Bianco Nascimento
(2017).
Exercise regulates expression of long noncoding RNAs.
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Wohlwend, Martin Rainer; Chawla, Konika; Wisløff, Ulrik & Moreira, Jose Bianco Nascimento
(2017).
Exercise regulates expression of long noncoding RNAs.
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Schaardenburgh, Michel van; Wohlwend, Martin Rainer; Rognmo, Øivind & Mattsson, Erney
(2016).
"Fem pluss" Legghevingstrening forbedrer gangdistanse hos pasenter med Clauducatio Intermittens.
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Wohlwend, Martin; Stølen, Tomas; Høydal, Morten; Wisløff, Ulrik & Rognmo, Øivind
(2014).
Exercise recovers mitochondrial function in left ventricle of rats inbred for low intrinsic running capacity.
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Wohlwend, Martin; Stølen, Tomas; Høydal, Morten; Wisløff, Ulrik & Rognmo, Øivind
(2013).
Aerobic interval training recovers differences in mitochondrial function between rats inbred for low- and high aerobic capacity.
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Wohlwend, Martin; Olsen, Alexander; Håberg, Asta & Palmer, Helen
(2012).
Investigating the reticular-activating hypofrontality model of acute exercise with Conner´s Continuous Performance test in combination with treadmill running and transcranial direct current stimulation.
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Wohlwend, Martin; Olsen, Alexander; Håberg, Asta & Palmer, Helen
(2012).
The effect of exercise on executive function – Investigating an alternative explanation for “Runner’s High”.
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Wohlwend, Martin; Moreira, Jose; Wisløff, Ulrik & Auwerx, Johan
(2021).
Exercise and the Dark Human Genome reveal Gene-targets in Age-related Diseases.
Norges teknisk-naturvitenskapelige universitet.
ISSN 9788232662951.
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Trening og det mørke genom avslører gen-targets i alders-relaterte sykdommer Konsekvensene av et aldrende samfunn er avhengig av en hovedfaktor: helse. Siden mennesker lever lenger og lenger mens helsen ikke følger denne trenden kommer aldringsrelaterte sykdommer til å bli en av våre største utfordringer ikke bare innenfor medisin men for hele samfunnet. Denne doktorgraden undersøker mulige strategier (trening og det mørke genom) for å identifisere nye gener som har et terapeutisk potensial for å motvirke de aldersrelaterte sykdommene hjertesvikt, diabetes og sarcopenia. Tidligere litteratur viser at trening har et enormt potensial for å øke hjerte- og skjelettmuskelhelsen. Men de molekylære mekanismene av trening er ikke godt utforsket. Kunstig aktivering av slike trenings-mekanismer kunne bli brukt som ny strategi for å levere noen spesifikke helsegevinster av trening. Med kartlegging av det menneskelige genom i 2003 har vi fått en annen gullgruve for å oppdage nye genetiske targets involvert i sykdommer. Det ble vist at 99% av DNAet ikke koder for proteiner. Siden denne delen av DNAet er ikke utforsket har den blitt kalt den «mørke siden av det menneskelige genom». Bemerkelsesverdig befinner seg de fleste genetiske variasjoner som er tilknyttet til vanlige sykdommer i enhancers som er en del av denne ikke-kodende delen. Dessuten finnes det en spesiell type store gener i denne ikke-kodende delen som blir transkribert men som translateres ikke: lange ikke-kodende RNA gener (lncRNAs). Først ble de tilsidesatt som cellulær søppel men nylig ble det rapportert at bare et slik RNA-molekyl kan forandre kromatin strukturen og dermed påvirke egenskaper i hele kroppen. På grunn av det attraktive potensialet av trening (Review Studie) og det ikke-kodende menneskelige genom for å finne nye gener med terapeutisk potensial for bekjempe aldringsrelaterte sykdommer, var målet av doktoravhandlingen: å teste om trening og hjertesvikt påvirker de samme genene som kan beskytte hjerteceller fra hypoksi (Studie I); å identifisere metabolske enhancers og deres target gener som forandrer aktiviteten sin på grunn av diabetes og innebærer en mutasjoner tilknyttet til metabolisme (Studie II); å utforske tangenten mellom trening og det mørke genom ved å lete etter og karakterisere en trenings-lncRNA (Studie III) i en aldringskontekst.
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Publisert
30. mai 2024 11:03
- Sist endret
30. mai 2024 11:03