Mitochondrial Uncoupling

Endelig har jeg begynt å forstå verdien i det de kaller Mitochondrial Uncoupling.

«Uncoupling» innbærer at mitokondriene produserer varme istedet for ATP. I denne prosessen produseres faktisk mer CO2 enn når mitokondriene produserer ATP (energi-molekyl). Overproduksjon av ATP skaper problemer i cellene. Jo mer ATP jo raskere vil cellen bli overstimulert og dø.

Det er «uncoupling» effekten som gir oss livsforlengelse. Jo større evne mitokondriene våre har til å bli «uncoupled», jo lenger vil vi leve.


 

Denne studien er en rapport fra et møte med 50 forskere som jobber med uncoupling. Den beskriver mye av det fysiologiske med 3 uncoupling proteiner, UPC1,UPC2 og UPC3. Det er UPC1 som gir termogenese(varme): http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1369193/

Uncoupling proteins: current status and therapeutic prospects

In bioenergetics, ‘uncoupling’ refers to any process through which energy released from the combustion of substrate (food) in the mitochondria is not conserved. The final steps in the oxidation of substrate are the transfer of electrons to oxygen, forming water, by the respiratory chain. The energy released is used by the respiratory chain to pump protons out of the mitochondria, as seen in Fig 1A. In most mitochondria, the majority of these protons re-enter through the ATP synthase, and the energy is used to synthesize ATP. However, if the protons re-enter by any other means, the mitochondria are considered to be uncoupled.

As energy in this process is transferred to heat and not stored as fat in the body, the activity of the uncoupling protein(s) can be viewed as an anti-obesity mechanism—a possibility that has attracted much attention, as both pharmaceutical companies and the general public are looking for easy ‘slimming’ agents.

 

Whether UCP1 needs an ‘activator’ is also a debated issue—however, it is agreed that an activator is necessary in the cell, with most scientists suggesting that fatty acids are good candidates. (Notat: fruktose er også en «aktivator»)

Uncoupling (measured as thermogenesis) is only observed when the cells are adequately stimulated, for example, by norepinephrine (Fig 1B).

However, it was the opinion of several participants at the meeting (in particular, E. Rial, Madrid, Spain, and J. Nedergaard, Stockholm, Sweden) that fatty acids do not participate in the uncoupling process. Instead, the fatty acids function only as anti-inhibitors by relieving the inhibition caused by the purine nucleotides (ATP and ADP) present in the cells—and experimentally by GDP in isolated brown-adipose mitochondria studies (Fig 1B)—prinicpally in accordance with suggestions by Nicholls from the 1970s.

The most discussed hypothesis at the meeting was that UCP2 and UCP3 do indeed function as uncoupling proteins, but only when oxidative stress (superoxide production) can be ameliorated by their activity. This is generally presented as the ‘mild-uncoupling’ hypothesis (Fig 2). It was debated whether this type of ‘not thermogenic but still membrane potential lowering activity’ is bioenergetically possible.

However, the oxidative-stress protection function is supported by the observation that macrophages from UCP2-null mice produce more superoxide, which results in a chronic activation of the NF-κB system with expected inflammatory consequences (S. Collins, Research Triangle Park, NC, USA). In addition, mice without UCP2 are more susceptible than normal mice to chemically induced colon cancer.

Brand suggested that the UCPs—whether or not this includes UCP1 is still open—specifically protect against oxidative damage caused by fatty acids, particularly polyunsaturated fatty acids from membrane phospholipids. These fatty acids can be attacked by mitochondrially-generated superoxide that converts them into 4-hydroxy-2-nonenal (HNE) and then interacts with the UCPs to make them able to conduct protons (or an equivalent). This ‘mild uncoupling’ would decrease the membrane potential and thus diminish the rate of production of superoxide; that is, this would be a self-regulating protective system.

Uncoupling protein 1. In mammals, UCP1 is found only in brown adipose tissue.

Uncoupling protein 2. UCP2 mRNA has been detected in macrophages, lymphocytes, thymocytes, pulmonary cells, enterocytes, adipocytes, pancreatic β-cells and certain neurons and, at a lower level, in liver, muscle and kidney cells. In the brain, UCP2 gene expression is generally low but high levels of UCP2 mRNA have been found in some regions, such as the limbic system and particular subdomains of the hypothalamus (D. Richard, Quebec, Canada).

Uncoupling protein 3. UCP3 expression levels in the skeletal muscle of animals or humans respond to changes in fatty-acid flux (F. Villarroya, Barcelona, Spain; Harper; Dulloo; Schrauwen).

The thyroid hormone tri-iodothyronine has a positive role in the control of UCP3 expression (F. Goglia, Benevento, Italy).


 

Denne studien fra 2002 beskriver de viktigste prisinippene for hva det vil si å ha evnen til å «uncouple» mitokondrienes energiproduksjon:

Living Fast, Dying When? The Link between Aging and Energetics

Her beskrives prosessen med proton-flyt (H+):

During oxidative phosphorylation electrons from reduced substrates are picked up by ubiquinone (Q) on complex 1 of the mitochondrial membrane. As these electrons are passed from complex 1 down the cytochromes the released energy is used to pump protons across the inner mitochondrial membrane creating a protonmotive force. Finally, in complex 4 the electron combines with a proton and oxygen to form water. The hydrogen ions pass back across the membrane via ATP synthase, resulting in the generation of ATP from ADP and inorganic phosphate, although occasionally protons leak back through the membrane without the creation of ATP, either as a membrane leak or via a specialized protein called an uncoupling protein (UCP), which allows the proton to pass uncoupled from the generation of ATP, but resulting in release of the stored energy as heat. Occasionally, however, this process goes wrong and the oxygen reacts with a reduced form of Q, called ubisemiquinone (QH), which results in generation of a superoxide free radical (O2) (6063).

Animals can reduce the levels of protonmotive force by increasing the extent of uncoupling in their mitochondria. To continue to generate ATP requires elevated oxygen consumption, although the net production of free-radical species is diminished. The animals uncouple respiration to increase their survival (63). This effect is diametrically opposed to the prevailing notion that increasing uncoupling should lead to an increase in free-radical production because of the elevated oxygen consumption (95). Our data are consistent with a protective effect of uncoupling respiration and, consequently, our current efforts are directed at resolving whether those MF1 mice with high-energy expenditures have more uncoupled mitochondria, or elevated levels of protection and repair processes.

http://m.jn.nutrition.org/content/132/6/1583S.long


 

Denne studiens overskrift (fra 2004) sier alt:

Uncoupled and surviving: individual mice with high metabolism have greater mitochondrial uncoupling and live longer

Mice in the upper quartile of metabolic intensities had greater resting oxygen consumption by 17% and lived 36% longer than mice in the lowest intensity quartile. Mitochondria isolated from the skeletal muscle of mice in the upper quartile had higher proton conductance than mitochondria from mice from the lowest quartile. The higher conductance was caused by higher levels of endogenous activators of proton leak through the adenine nucleotide translocase and uncoupling protein-3. Individuals with high metabolism were therefore more uncoupled, had greater resting and total daily energy expenditures and survived longest – supporting the ‘uncoupling to survive’ hypothesis.

The work we performed on mitochondria extracted from the second and third cohorts of mice, in combination with the first cohort [Fig. 1] where we showed that mice with higher metabolic intensities lived longest, provide greater support for the ‘uncoupling to survive’ hypothesis than for the ‘rate of living-free-radical damage’ hypothesis, at the level of individual phenotypic differences in metabolic intensity. Since we used an outbred strain kept in constant environmental conditions, presumably these phenotypic differences have a genetic component at their origin; this conclusion is supported by the fact that the same association between longevity and metabolic intensity is also observed across inbred strains (Storer et al., 1967).

http://onlinelibrary.wiley.com/doi/10.1111/j.1474-9728.2004.00097.x/full


 

Denne studien fra 1993 nevner at «uncoupled» mitkondria produserer mer CO2:

Characterization of the folate-dependent mitochondrial oxidation of carbon 3 of serine.

In contrast, CO2 production was greatest in uncoupled mitochondria and lowest in respiratory-inhibited mitochondria.

http://www.ncbi.nlm.nih.gov/pubmed/8485144/

Treating Diabetes with Exercise – Focus on the Microvasculature

Veldig viktig studie som nevner at det ikke finnes glatt muskulatur i kapillærene, så det er arteriolene som avgjør blodsirkulasjonen i kapillærene. His blodsirkulasjonen i en arteriole blir dårlig stopper sirkulasjonen opp i et område av muskelen som serveres av kapillærene.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4000229

Abstract

The rising incidence of diabetes and the associated metabolic diseases including obesity, cardiovascular disease and hypertension have led to investigation of a number of drugs to treat these diseases. However, lifestyle interventions including diet and exercise remain the first line of defense. The benefits of exercise are typically presented in terms of weight loss, improved body composition and reduced fat mass, but exercise can have many other beneficial effects. Acute effects of exercise include major changes in blood flow through active muscle, an active hyperemia that increases the delivery of oxygen to the working muscle fibers. Longer term exercise training can affect the vasculature, improving endothelial health and possibly basal metabolic rates. Further, insulin sensitivity is improved both acutely after a single bout of exercise and shows chronic effects with exercise training, effectively reducing diabetes risk. Exercise-mediated improvements in endothelial function may also reduce complications associated with both diabetes and other metabolic disease. Thus, while drugs to improve microvascular function in diabetes continue to be investigated, exercise can also provide many similar benefits on endothelial function and should remain the first prescription when treating insulin resistance and diabetes. This review will investigate the effects of exercise on the blood vessel and the potential benefits of exercise on cardiovascular disease and diabetes.

At rest, a low proportion of capillaries are exposed to blood flow at one time, with a rapid increase in the number of perfused capillaries after exercise [31], thus increasing functional capillary density.

Vascular smooth muscle cells are located around the arterioles and some venules, and can constrict to change blood flow patterns, while capillaries do not typically contribute to blood flow changes [30] (Figure 1). Blood flow through capillaries is controlled upstream by small arterioles at rest, and the rapid recruitment of unperfused capillaries by exercise could suggest that nerves are responsible for this action [34]. The sympathetic nervous system is mainly responsible for the vasoconstrictor responses, and as the arterioles and larger vessels are innervated [38] the majority of sympathetic nervous system activity is localized to that area of the vascular tree. Physical exercise can enhance sympathetic nerve activity [39] to maintain arterial pressure, and may be involved in maintaining exercise tolerance, as reviewed by Thomas and Segal [38].

Structural differences between artery, arteriole and capillary. No vascular smooth muscle is located on the capillary; therefore flow through capillaires is modified by pre-capillary arterioles. Cessation of flow through arterioles will prevent flow through a portion of the muscle.

Insulin relies on endothelium-dependent vasodilation to enhance perfusion, thus endothelial dysfunction reduces insulin-mediated increases in muscle perfusion, which can contribute to the metabolic deficit in diabetes. As exercise-mediated changes in perfusion are typically endothelium-independent, exercise is still able to recruit capillaries and thus increase muscle perfusion in obesity and type 2 diabetes, even in the face of endothelial dysfunction. Numerous studies have now shown that while insulin’s vascular effects may be blocked in diabetes, exercise still maintains its ability to increase the distribution of blood flow through muscle [42].

Nitric oxide (NO) is the main vasodilator from the endothelium specifically involved in blood flow and blood distribution, and while reduction in nitric oxide synthesis lowered total blood flow, exercise-mediated capillary recruitment was not affected [46]. In fact, inhibition of NO formation enhances both resting and exercise-mediated muscle oxygen uptake [47]; despite a reduction in total flow, microvascular flow was not affected, suggesting that NO is not involved in the vascular response to exercise.

The distribution of blood through muscle increases the capacity for nutrient exchange. In exercise the primary purpose of functional hyperemiais for oxygen delivery, as the oxygen required by exercising muscle is much higher than resting muscle (reviewed in [37]). Recruitment of capillaries can decrease the velocity of blood flow by increasing the cross-sectional area of the capillary bed and the time available for exchange. Recruitment also increases surface area for exchange and decreases perfusion distances to promote oxygen delivery to tissues with exercise [34] (Figure 2). While in exercise the main metabolite required at the working muscle is oxygen, distribution of other nutrients can also be affected, including glucose, fats, other hormones and cytokines. Muscle metabolism can therefore be altered by perfusion of the tissue [48,49]. While there can be regulated transport of certain larger hormones across the vasculature [50,51], smaller molecules can diffuse across the endothelium easily, possibly making muscle perfusion a more important player in the delivery of glucose and oxygen to the tissue.

Vasodilation affects delivery, and thus metabolism. The rate of transfer across the endothelium is dependent on surface area, permeability of the endothelium, diffusion distance, and concentration difference (Fick’s first law of diffusion). Vasodilation increases surface area in arterioles for exchange, but will also recruit downstream capillaries, which will reduce diffusion distance and increase surface area for exchange. Working muscle increases oxygen utilization, increasing the concentration difference from the blood vessel to the tissue.

Mitochondrial dysfunction has been proposed to be both a cause [72] and a consequence [73] of insulin resistance, and may contribute to endothelial dysfunction [74]. If oxygen delivery is a component of mitochondrial health and biogenesis, it is possible that impaired perfusion may contribute to fiber type switching, where an oxidative fiber, which is typically highly vascularized and contains mitochondria, switches to a glycolytic fiber with less vascularity and mitochondria. As exercise can improve oxidative capacity, increase mitochondria content [75], and also increase muscle perfusion [31,32,34,45,76], the relationship between muscle perfusion, fiber type and mitochondrial function needs to be clarified.

The vascular component of exercise may well be linked to the reduction of diabetic complication such as retinopathy, peripheral neuropathy and nephropathy, as there is a vascular basis to many of these complications. The endothelium has been implicated in diabetic nephropathy [88], and the blood vessels formed in response to reduced perfusion in retinopathy show abnormal structure and function [89].

CO2-beriket vann til fotbad

Å bade i CO2 beriket vann har vært brukt som medisin i alle år. Hellige og mirkauløse kilder har ofter vært vann med et høyt innhold av karbondioksid. Og det har blitt brukt i spa behandling i århundrer, spesielt i Bulgaria. Man finner Co2-rikt vann spesielt ved sovende og inaktive vulkaner.

CO2 er et veldig lite molekyl som diffunderer lett igjennom huden. I CO2-beriket vann kommer derfor CO2 inn i huden og inn til blodkarene i underhuden, hvor alle sansenerver ligger. Den økte CO2 en gjør at blodkarene rundt nervetrådene og i muskelvevet utvides (vasodilasjon) og at oksygene letter hopper av blodcellene slik at det kan bli brukt til energi i celler som vanligvis har lite tilgang på oksygen.

CO2 beriket vann kan vi lage selv på en svært enkel måte: blande Natron, Sitronsyre og vann. Begge disse stoffene fåes kjøpt på vanlig daglivarebutikk. Vannet begynner å bruse, og dette er CO2.

Studier nevner at man bør ha 900-1200 mg CO2 pr liter vann. Ved å måle pH kan vi regne med at vi har det når pH er nede på 5.

Vi kan se CO2 effekten på huden ved at det kommer tett-i-tett med ørsmå bobler. I f.eks. fotbad vil vi se at når vi tar foten opp fra vannet så er den rød, noe som er et tegn på økt blodsirkulasjon i huden.

For alle med nevropatier, diabetes, sår, nevromer, leggspenninger, restless leg syndrom, som lett blir sliten i bena av å gå, så vil dette være verdt et forsøk.

2-3 ganger i uka pleier å være den vanlige oppskriften. Noen studier har brukt det hver dag i mange uker. Spesielt når det gjelder diabetes sår.

Oppskrift: Bland 1 poseNatron med 2 poser Sitronsyre (blandingsforhold ca. 1:1) og hell innholdet i 5L vann. Det bruser veldig pga reaksjonen som lager CO2. Når du setter føttene nedi skal det komme mange små bobler som dekker huden. Etter 5-10 minutter vil huden som er under vann bli rød. Dette er et tegn på økt blodsirkulasjon.

5-15 minutter etter du er ferdig med fotbadet vil du sannsynligvis kjenne det prikker og strømmer ellers i kroppen også. Vanligvis kjennes det først og fremst i armer og bein, som er de stedene vi lettest kjenner økt blodsirkulasjon.

Her er noen studier som bekrefter effektene av CO2 beriket vann.

Beskriver det meste om balneotherapy, som det også heter. Inkludert kontraindikasjoner(hjerteproblemer og hypercapni som følge av lungeskade): http://www.centro-lavalle.com/edu/wp-content/uploads/2010/05/Carbon_Dioxide_Bath.pdf

Table 4. Major Indicators for CO2 Balneotherapy

1. Hypertension, especially borderline hypertension

2. Arteriolar occlusion, Stages I and II

3. Functional arteriolar blood flow disorders

4. Microcirculatory disorders

5. Functional disorders of the heart

Beskriver alt om hvordan det øker blodsirkulasjon og oksygenmetning: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3169585/?report=classic

Viser at det øker blodsirkulasjonen i huden og oksygenmetningen i muskelvev hos de som lett blir trøtte i beina: http://www.ncbi.nlm.nih.gov/pubmed/9112881/

Viser at det øker blodsirkulasjon og produksjonen av blodkar (angiogenese): http://circ.ahajournals.org/content/111/12/1523.long

Viser at det reparerer sår som ikke vil gro: http://iv.iiarjournals.org/content/24/2/223.long

Viser at det reparerer muskelskade: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3805014/

Viser at det reparerer muskelskade og atrofi (muskelsvikt) etter langtids post-operative sengeliggende: http://www.ncbi.nlm.nih.gov/pubmed/21371433

Viser at det reduserer hjertefrekvens gjennom å dempe sympaticus aktivering (ikke ved å øke parasymptaticus aktivering): http://jap.physiology.org/content/96/1/226

Viser at det øker mitokondrier og fjerner syster: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3499556/

Viser at det øker antioksidant status, reduserer frie radikaler og øker blodsirkulasjon i kapuillærene (mikrosirkulasjon): http://www.ncbi.nlm.nih.gov/pubmed/21248668

Viser at det hjelper til å reparere sår etter operasjon: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3595724/

Dr. Sircus sin forklaring av CO2 medisin som nevner mange måter å gjøre det på: http://drsircus.com/medicine/co2-medicine-bath-bombing-your-way-to-health

Denne artikkelen beskriver mye om historien til CO2-bad. http://ndnr.com/dermatology/cellulite-and-carbon-dioxide-bath/

Mange bilder av diabetes sår (OBS: ikke for sarte sjeler) som blir regenerert i løpet av få uker med 20-30 min fotbad. Disse bruker 900-1000ppm CO2 konsentrasjon. Jeg er usikker på om det er mulig med å blande Sitronsyre og Natron: http://www.iasj.net/iasj?func=fulltext&aId=48581

Denne artikkelen beskriver de fleste sider ved forskjellig bruk av CO2 behandling. God gjennomgang av hvordan blodsirkluasjonen påvirkes. http://www.scuolaeuropeamedicinaestetica.it/public/CARBOXYTHERAPY.pdf

Preventing overtraining in athletes in high-intensity sports and stress/recovery monitoring

Nevner de fleste faktorene rundt restitusjon. Og legger vekt på at idrettsutøvere er under-restituert heller enn over-trent. Beskriver spørreskjemaet RESTQ-Sport som kan brukes til å følge med på restitusjonseffekten hos en idrettsutøver.

http://onlinelibrary.wiley.com/doi/10.1111/j.1600-0838.2010.01192.x/full

The key defining features are

  • Recovery is a process in time and is dependent on the type of and duration of stress.
  • Recovery depends on a reduction of stress, a change of stress, or a break from stress.
  • Recovery is specific to the individual and depends on individual appraisal.
  • Recovery can be passive, active, or pro-active.
  • Recovery is closely tied to situational conditions.

Furthermore, Kellmann und Kallus (2001) defined recovery as

an inter-individual and intra-individual multi-level (e.g., psychological, physiological, social) process in time for the re-establishment of performance abilities. Recovery includes an action-oriented component, and those self-initiated activities (proactive recovery) can be systematically used to optimize situational conditions and to build up and refill personal resources and buffers (p. 22).

This definition also demonstrates the complexity of recovery, as discussed in more detail by Kellmann (2002a), and highlights the need to individually tailor recovery activities.

The RESTQ-Sport consists of 77 items (19 scales with four items each plus one warm-up item), which the participants answer retrospectively. A Likert-type scale is used with values ranging from 0 (never) to 6 (always) indicating how often the respondent participated in various activities during the past 3 days/nights. High scores in the stress-associated activity scales reflect intense subjective stress, whereas high scores in the recovery-oriented scales indicate good recovery activities.

The RESTQ-Sport consists of seven general stress scales (General Stress, Emotional Stress, Social Stress, Conflicts/Pressure, Fatigue, Lack of Energy, Physical Complaints), five general recovery scales (Success, Social Recovery, Physical Recovery, General Well-being, Sleep Quality), three sport-specific stress scales (Disturbed Breaks, Emotional Exhaustion, Injury), and four sport-specific recovery scales (Being in Shape, Personal Accomplishment, Self-Efficacy, Self-Regulation). Examples of items would be: “In the past (3) days/nights … my body felt strong” (for the scale Being in Shape) or “In the past (3) days/nights … I had a satisfying sleep” (for the scale Sleep Quality).

When talking to coaches, it appears easier to frame the current topic as underrecovery rather than overtraining. It is the coaches’ job to train athletes at the optimal level (which is often at the limit); however, they should also avoid overtraining. Coaches may be much more receptive to working with the concept of underrecovery because it acknowledges that underrecovery can also be due to factors, which are outside of their control. The diagnosis of overtraining and underrecovery, should be determined only by an interdisciplinary team that is able and willing to share the data to allow for a comprehensive assessment of the athlete. To optimize this process, the consultation of athletes should be conducted in consultation with coaches, sport physicians, and sport psychologists. Consequently, all physiological and psychological data, as well as training and performance data should be shared on an interdisciplinary basis (Kellmann, 2002a; Smith & Norris, 2002). Assessment should include a complete training documentation, the assessment of subjective and objective physiological and psychological data, and the integration of an athletes’ perspective. It is important that psychological testing like lactate testing, also be part of the regular training routine. Furthermore, research in sport psychology should systematically focus on psychological interventions, which help to optimize the recovery process, ideally in combination with physiological interventions.

Is recovery driven by central or peripheral factors? A role for the brain in recovery following intermittent-sprint exercise

Nevner svært mye spennende om stølhet (DOMS). Spesielt om hvor mye central sensitering har å si, og mye om hydrering (vann). Samt alt om betennelser og andre faktorer knyttet til DOMS. Sier bl.a. at glucogenlagre normaliseres etter 24 timer uavhengig av hva man spiser, men glykogen omsetningen i kroppen er begrenset i 2-3 dager etter. Nevner også at det er alle de perifere faktorene, sammen med de sentrale, som tilsammen skaper DOMS tilstanden.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3909945/

Abstract

Prolonged intermittent-sprint exercise (i.e., team sports) induce disturbances in skeletal muscle structure and function that are associated with reduced contractile function, a cascade of inflammatory responses, perceptual soreness, and a delayed return to optimal physical performance. In this context, recovery from exercise-induced fatigue is traditionally treated from a peripheral viewpoint, with the regeneration of muscle physiology and other peripheral factors the target of recovery strategies. The direction of this research narrative on post-exercise recovery differs to the increasing emphasis on the complex interaction between both central and peripheral factors regulating exercise intensity during exercise performance. Given the role of the central nervous system (CNS) in motor-unit recruitment during exercise, it too may have an integral role in post-exercise recovery. Indeed, this hypothesis is indirectly supported by an apparent disconnect in time-course changes in physiological and biochemical markers resultant from exercise and the ensuing recovery of exercise performance. Equally, improvements in perceptual recovery, even withstanding the physiological state of recovery, may interact with both feed-forward/feed-back mechanisms to influence subsequent efforts. Considering the research interest afforded to recovery methodologies designed to hasten the return of homeostasis within the muscle, the limited focus on contributors to post-exercise recovery from CNS origins is somewhat surprising. Based on this context, the current review aims to outline the potential contributions of the brain to performance recovery after strenuous exercise.

recovery strategies might be broadly differentiated as being either physiological (e.g., cryotherapy, hydrotherapy, massage, compression, sleep), pharmacological (e.g., non-steroidal anti-inflammatory medications) or nutritional (e.g., dietary supplements), all mean to limit continued post-exercise disturbances and inflammatory events within the exercised muscle cells. This peripheral focus emphasizes the importance of an accelerated return of structural integrity and functional capacity from below the neuromuscular junction.

Conceptually, if the brain is held as central to the process of performance declines (i.e., fatigue), it stands to reason that it would also have some role in post-exercise recovery (De Pauw et al., 2013).

Classically defined as an exercise-induced reduction in force generating capacity of the muscle, fatigue may be attributed to peripheral contractile failure, sub-optimal motor cortical output (supraspinal fatigue) and/or altered afferent inputs (spinal fatigue) innervating the active musculature (Gandevia, 2001).

Alternatively, concepts of residual fatigue remain predominately within the domain of peripherally driven mechanisms, such as blood flow, muscle glycogen repletion and clearance of metabolic wastes (Bangsbo et al., 2006).

The physical and biochemical changes observed during intermittent-sprint exercise have traditionally been interpreted in terms of metabolic capacity (Glaister, 2005). Indeed, lowered phosphocreatine concentrations (Dawson et al., 1997), reduced glycolytic regeneration of ATP (Gaitanos et al., 1993) and increasing H+ accumulation (Bishop et al., 2003) have all been associated with declining intermittent-sprint performance.

While reductions in muscle excitability after intermittent-sprint exercise have also been observed (Bishop, 2012), metabolic perturbations are rapidly recovered within minutes (Glaister, 2005).

The ultimate indicator of post-exercise recovery is the ability of the muscle to produce force i.e., performance outcomes.

Reductions in skeletal muscle function after intermittent-sprint exercise are often proposed to be caused by a range of peripherally-induced factors, including: intra-muscular glycogen depletion; increased muscle and blood metabolites concentrations; altered Ca++ or Na+-K+ pump function; increased skeletal muscle damage; excessive increases in endogenous muscle and core temperatures; and the reduction in circulatory function via reduced blood volume and hypohydration (Duffield and Coutts, 2011; Bishop, 2012; Nédélec et al., 2012).

Conversely, Krustrup et al. (2006) reported declines in intramuscular glycogen of 42 ± 6% in soccer players, with depleted or almost depleted glycogen stores in ~55% of type I fibers and ~25–45% of type II fibers reasoned to explain acute declines in sprint speed post-match. Importantly, muscle glycogen resynthesis after team sport activity is slow and may remain attenuated for 2–3 days (Nédélec et al., 2012). Such findings highlight the importance of nutrition in post-exercise recovery (Burke et al., 2006); yet it is noteworthy that muscle glycogen stores remain impaired 24 h after a soccer match, irrespective of carbohydrate intake and should be recognized as a factor in sustained post-match suppression of force (Bangsbo et al., 2006; Krustrup et al., 2011).

Mechanical disruptions to the muscle fiber are task dependant, though likely relate to the volume of acceleration, deceleration, directional change and inter-player contact completed (i.e., tackling or collisions) (McLellan et al., 2011; Duffield et al., 2012). Importantly, EIMD manifests in reduced voluntary force production that has been associated with the elevated expression of intracellular proteins (e.g., creatine kinase and C-reactive protein), swelling, restricted range of motion and muscle soreness (Cheung et al., 2003). Whilst it is generally accepted that lowering blood-based muscle damage profiles may hasten athletic recovery, mechanisms explaining the return of skeletal muscle function are somewhat ambiguous (Howatson and Van Someren, 2008).

Interestingly, markers of EIMD are also not closely associated with muscle soreness (Nosaka et al., 2002; Prasartwuth et al., 2005), though perceptual recovery is reportedly related with the recovery of maximal sprint speed (Cook and Beaven, 2013). While this raises questions in terms of the physiological underpinnings of muscle soreness, weaker relationships between EIMD and neuromuscular performance may suggest the potential for other drivers of recovery outside of peripheral (muscle damage or metabolic) factors alone.

Finally, while the relationship between hydration status and intermittent-sprint performance remains contentious (Edwards and Noakes, 2009), fluid deficits of 2–4% are common following team-sport exercise (Duffield and Coutts, 2011). Mild hypohydration reportedly demonstrates limited effects on anaerobic power and vertical jump performance (Hoffman et al., 1995; Cheuvront et al., 2006); however, some caution is required in interpreting these data as these testing protocols reflect only select components of team sport performance.

Nevertheless, the role of hydration in recovery should not be overlooked as changes in extracellular osmolarity are suggested to influence glucose and leucine kinetics (Keller et al., 2003). Further, the negative psychological associations (conscious or otherwise) derived from a greater perceptual effort incurred in a hypohydrated state may impact mental fatigue (Devlin et al., 2001; Mohr et al., 2010).

Rather, that the integrative regulation of whole body disturbances based on these peripheral factors, alongside central regulation may be relevant.

Bench-to-bedside review: Permissive hypercapnia

Nevner veldig mye rundt hva hyperkapni kan brukes til i klinisk sammenheng, men spesielt interessant er kapittelet om hvordan det reduserer oksidativt stress, som forklarer godt og omfattende dette prinsippet.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1065087/

Effects on free radical generation and activity

Hypercapnic acidosis appears to attenuate free radical production and modulate free radical induced tissue damage. In common with most biological enzymes, the enzymes that produce these oxidizing agents function optimally at neutral physiological pH levels. Oxidant generation by both basal and stimulated neutrophils appears to be regulated by ambient carbon dioxide levels, with oxidant generation reduced by hypercapnia and increased by hypocapnia [54]. The production of superoxide by stimulated neutrophils in vitro is decreased at acidic pH [6567]. In the brain, hypercapnic acidosis attenuates glutathione depletion and lipid peroxidation, which are indices of oxidant stress [39]. In the lung, hypercapnic acidosis has been demonstrated to reduce free radical tissue injury following pulmonary ischaemia/ reperfusion [27]. Hypercapnic acidosis appears to attenuate the production of higher oxides of nitric oxide, such as nitrite and nitrate, following both ventilator-induced [26] and endotoxin-induced [29] ALI. Hypercapnic acidosis inhibits ALI mediated by xanthine oxidase, a complex enzyme system produced in increased amounts during periods of tissue injury, which is a potent source of free radicals [68] in the isolated lung [24]. In in vitro studies the enzymatic activity of xanthine oxidase was potently decreased by acidosis, particularly hypercapnic acidosis [24,25].

Concerns exist regarding the potential for hypercapnia to potentiate tissue nitration by peroxynitrite, a potent free radical. Peroxynitrite is produced in vivo largely by the reaction of nitric oxide with superoxide radical, and causes tissue damage by oxidizing a variety of biomolecules and by nitrating phenolic amino acid residues in proteins [6973]. The potential for hypercapnia to promote the formation of nitration products from peroxynitrite has been clearly demonstrated in recent in vitroexperiments [45,51]. However, the potential for hypercapnia to promote nitration of lung tissue in vivoappears to depend on the injury process. Hypercapnic acidosis decreased tissue nitration following pulmonary ischaemia/reperfusion-induced ALI [27], but it increased nitration following endotoxin-induced lung injury [29].

 

The Role of Carbon Dioxide in Free Radical Reactions of the Organism

Nevner flere måter som CO2 virker som en antioksidant, i tillegg som en beskytter av andre antioksidanter. Dette er en teorietisk gjennomgang.

http://www.biomed.cas.cz/physiolres/pdf/51/51_335.pdf

Summary

Carbon dioxide interacts both with reactive nitrogen species and reactive oxygen species. In the presence of superoxide, NO reacts to form peroxynitrite that reacts with CO2 to give nitrosoperoxycarbonate. This compound rearranges to nitrocarbonate which is prone to further reactions. In an aqueous environment, the most probable reaction is hydrolysis producing carbonate and nitrate. Thus the net effect of CO2 is scavenging of peroxynitrite and prevention of nitration and oxidative damage. However, in a nonpolar environment of membranes, nitrocarbonate undergoes other reactions leading to nitration of proteins and oxidative damage. When NO reacts with oxygen in the absence of superoxide, a nitrating species N2O3 is formed. CO2 interacts with N2O3 to produce a nitrosyl compound that, under physiological pH, is hydrolyzed to nitrous and carbonic acid. In this way, CO2 also prevents nitration reactions. CO2 protects superoxide dismutase against oxidative damage induced by hydrogen peroxide. However, in this reaction carbonate radicals are formed which can propagate the oxidative damage. It was found that hypercapnia in vivo protects against the damaging effects of ischemia or hypoxia. Several mechanisms have been suggested to explain the protective role of CO2 in vivo. The most significant appears to be stabilization of the iron-transferrin complex which prevents the involvement of iron ions in the initiation of free radical reactions.

CO2 er en antioksidant