An acid-sensing ion channel that detects ischemic pain

Nevner mange interessante ting om hvordan lav pH som følge av CO2 ikke er det samme som lav pH som følge av f.eks. melkesyre(laktic acid). De sier at melkesyre og ATP må være sammen for å gjøre pH-sensitive nerver aktive. Noe som skjer ved hard trening hvor ATP lekker ut fra muskel cellene. Laktat aktiverer ASICs umiddelbart, mens ATP er «treg» og det skjer i løpet av 30-60 sekunder. Kanskje denne overaskelsen i nervesystemet er utgangspunktet for sentralsensiteringen som skjer ved DOMS?

Paradox number 2 answered: coincident detection of lactate, ATP and acid

We are left with a seemingly more profound paradox: how can acid be relevant to ischemic pain if no pain is caused by metabolic events such as hypercapnia that can cause the same kind of pH change that occurs during a heart attack? Pan et al. (13) demonstrated the paradox most convincingly. They measured the pH on the surface of the heart when a coronary artery was blocked and found that it dropped from pH 7.4 to 7.0. Then they reperfused the artery and had the animal breathe carbon dioxide until the resulting hypercapnia dropped the pH of the heart to 7.0. The blockade of the artery caused increased firing of sensory axons that innervate the heart, but the hypercapnia did not. How can this observation be reconciled with their other result (see above) that buffering extracellular pH greatly diminishes axon firing during artery occlusion? The simple interpretation is that protons must be necessary to activate the sensory axons, but cannot by themselves be sufficient. In other words, something must act together with protons to activate the axons.

We searched for compounds released during ischemia that might act together with protons to activate ASIC3. We found two: lactate and adenosine 5′-triphosphate (ATP). When the channel is activated by pH 7.0 in the presence of 15 mM lactate, the resulting current is 80% greater than when lactate is absent (Figure 6). These are physiological values. Under resting conditions, extracellular lactate is about 1 mM in skeletal muscle; after extreme ischemic exercise it rises to 15-30 mM (26). The increased current in the presence of lactate makes the channel better at sensing the lactic acidosis that occurs in ischemia than other kinds of acidosis such as the carbonic acidosis when an animal breathes CO2.

Extracellular ATP rises to >10 µM when a muscle contracts without blood flow (27). We find that a transient appearance of such extracellular ATP can greatly increase ASIC3 current even for minutes after the ATP is removed (Figure 7).

Though they both increase ASIC3 current, lactate and ATP have qualitatively different effects. Lactate acts immediately and must be present for the ASIC current to be enhanced. ATP increases the current slowly – a peak is reached between 15 s and 1 min after ATP is applied – and the effect persists for minutes after ATP is removed. Also, lactate acts on every cell that expresses ASIC3 whereas ATP acts on some cells but not others. We find that lactate acts by altering the basic gating of the channel, which, surprisingly, involves binding of calcium in addition to protons (28). In contrast, the ATP binding site must not be the ASIC3 channel itself; there are a variety of purinergic receptors, some of which are ion channels and some of which are G-protein-coupled receptors. We are presently asking if any of these known receptors might mediate ATP modulation of ASIC3.

Vibration Therapy in Management of Delayed Onset Muscle Soreness (DOMS).

Svært interessant studie på hvordan vibrasjon (percussor) hjelper mot smerte og stølhet. Den snakker mest om whole-body-vibration, som f.eks. på en Vibroplate. Men de fleste fysiologiske effektene gjelder også for lokal vibrasjon som gis av en Percussor.

Hele studien her:


Both athletic and nonathletic population when subjected to any unaccustomed or unfamiliar exercise will experience pain 24-72 hours postexercise. This exercise especially eccentric in nature caused primarily by muscle damage is known as delayed-onset muscle soreness (DOMS). This damage is characterized by muscular pain, decreased muscle force production, reduce range of motion and discomfort experienced. DOMS is due to microscopic muscle fiber tears. The presence of DOMS increases risk of injury. A reduced range of motion may lead to the incapability to efficiently absorb the shock that affect physical activity. Alterations to mechanical motion may increase strain placed on soft tissue structures. Reduced force output may signal compensatory recruitment of muscles, thus leading to unaccustomed stress on musculature. Differences in strength ratios may also cause excessive strain on unaccustomed musculature. A range of interventions aimed at decreasing symptoms of DOMS have been proposed. Although voluminous research has been done in this regard, there is little consensus among the practitioners regarding the most effective way of treating DOMS. Mechanical oscillatory motion provided by vibration therapy. Vibration could represent an effective exercise intervention for enhancing neuromuscular performance in athletes. Vibration has shown effectiveness in flexibility and explosive power. Vibration can apply either local area or whole body vibration. Vibration therapy improves muscular strength, power development, kinesthetic awareness, decreased muscle sore, increased range of motion, and increased blood flow under the skin. VT was effective for reduction of DOMS and regaining full ROM. Application of whole body vibration therapy in postexercise demonstrates less pressure pain threshold, muscle soreness along with less reduction maximal isometric and isokinetic voluntary strength and lower creatine kinase levels in the blood.


Cutaneous Receptors Responses: The sensation of pressure and touch is masked during vibration [20], and also postvibration [21]. Some cutaneous mechanoreceptor afferents get aroused for many minutes postvibration [21] and this may be the physiological reason for the tingling sensation often experienced postvibration. On the basis of gate control hypothesis [22] we can infer that vibration strongly impacts affrents discharge from fast adapting mechanoreceptors and muscle spindles and hence become an effective pain reliever.

Pain Perception Responses: Vibration can be used as transcutaneous electrical nerve stimulation (TENS) [23] to reduce the perception of pain [7]. Passive vibration has reduced pain in 70% of patients with acute and chronic musculoskeletal pain [24] and passive 80 Hz vibration has been shown to reduce pain caused by muscle pressure [25]. More recent evidence suggests that pain perception in DOMS depends partly on fast myelinated afferent fibres, which are distinct from those that convey most other types of pain [26].

Lundeberg et al., concluded that vibration relieved pain by activating the large diameter fibres while suppressing the transmission activity in small diameter fibres [24,28].

Vibration therapy leads to increase of skin temperature and blood flow [30].


Microvascular Perfusion Changes in the Contralateral Gastrocnemius Following Unilateral Eccentric Exercise

Spennende studie som nevner at blodsirkulasjonen øker i området som har stølhet. Og den økte blodsirkulasjonen vedvarer i mer enn 48 timer etter treningen. I dette tilfellet i leggen som ble trent. De mener det er pga økt betennelse i muskelen.


There was a significant main effect for time for blood volume (p=0.023) and blood flow (p=0.010), with no significant difference in blood flow velocity (p=0.316). There were significant increases in blood volume (p=0.001) and blood flow (p<0.001) immediately postexercise (9.77 ± 3.19 dB and 3.53 ± 0.86 dB/sec), respectfully in the contralateral limb compared to baseline (6.18 ± 2.05 dB and 2.40 ± 0.69), with no change in blood flow velocity (p=0.487). The effect size for blood volume was 1.34 (0.09, 2.60) and blood flow was 1.41 (0.15, 2.68). The increases in contra lateral blood volume (p=0.002) and blood flow (p=0.003) were maintained at 48 hours (9.41 ± 1.90 dB and 3.51 ± 0.47 dB/sec) compared to baseline, with again no change in blood flow velocity (p=0.411). The effect size for blood volume was 1.62 (0.32, 2.92) and blood flow was 1.86 (0.51, 3.22). There were no changes in blood volume (p=0.814), blood flow (p=0.962), or blood flow velocity (p=0.493) between post-exercise and 48 hours for the contra lateral limb.

Following eccentric exercise to a single limb, the contralateral limb resulted in increased blood volume and blood flow immediately after exercise and at 48 hours post exercise. From previous research in our lab [12] immediately after eccentric exercise, blood volume and blood flow increased in the exercise leg by 42% and 80%, respectfully. From this study, the contra lateral leg increased 17% and 35% for blood volume and blood flow, respectfully. This finding supports earlier work by Seals [7] and Taylor et al. [8] that identified vasodilatation of the contra lateral limb after exercise initiation. Blood flow velocity did not change in the contra lateral limb after exercise and at 48 hours. Since this limb was not exercised, recruitment of capillaries is not necessary, as would be in exercised muscle [14].

Eccentric exercise increased microvascular perfusion immediately after exercise in the contralateral limb, which had not been examined before. The increased perfusion was maintained over 48 hours, so the prolonged increased in perfusion of the contralateral limb may have been due to an inflammatory response or the extra demands placed on the contralateral limb for support during walking.

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.

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.


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.

Carbon dioxide and the critically ill—too little of a good thing?

Omfattende studie av alle de gode egenskapene ved hyperkapni – høyt CO2 nivå. Nevner mange interessante ting, bl.a. at CO2 indusert acidose gir mye mindre fire radikaler enn om pH senkes av andre faktorer. Bekrefter også at oksygen blir sittende fast på blodcellene ved hypokapni, og at melkesyreproduksjonen begrensens når acidosen er pga CO2 men ikke når den er av andre faktorer.

Spesielt med denne artikkelen er at den beskriver forskjellene på en hyperkapni acidose og acidose av andre faktorer. Hyperkapnisk acidose har beskyttende egenskaper.

Permissive hypercapnia (acceptance of raised concentrations of carbon dioxide in mechanically ventilated patients) may be associated with increased survival as a result of less ventilator-associated lung injury.
Accumulating clinical and basic scientific evidence points to an active role for carbon dioxide in organ injury, in which raised concentrations of carbon dioxide are protective, and low concentrations are injurious.
Although hypercapnic acidosis may indicate tissue dysoxia and predict adverse outcome, it is not necessarily harmful per se. In fact, it may be beneficial. There is increasing evidence that respiratory (and metabolic) acidosis can exert protective effects on tissue injury, and furthermore, that hypocapnia may be deleterious.
If hypoventilation is allowed in an effort to limit lung stretch, carbon dioxide tension increases. Such “permissive hypercapnia” may be associated with increased survival in acute respiratory distress syndrome (ARDS);2 this association is supported by outcome data from a 10-year study.3
Furthermore, hypocapnia shifts the oxyhaemoglobin dissociation curve leftwards, restricting oxygen off-loading at the tissue level; local oxygen delivery may be further impaired by hypocapnia-induced vasoconstriction.
Brain homogenates develop far fewer free radicals and less lipid peroxidation when pH is lowered by carbon dioxide than when it is lowered by hydrochloric acid.19
Finally, greater inhibition of tissue lactate production occurs when lowered pH is due to carbon dioxide than when it is due to hydrochloric acid.20
An association between hypoventilation, hypercapnia, and improved outcome has been established in human beings.2521 In lambs, ischaemic myocardium recovers better in the presence of hypercapnic acidosis than metabolic acidosis.22 Hypercapnic acidosis has also been shown to protect ferret hearts against ischaemia,23 rat brain against ischaemic stroke,16 and rabbit lung against ischaemia-reperfusion injury.24 Hypercapnia attenuates oxygen-induced retinal vascularisation,25 and improves retinal cellular oxygenation in rats.26 “pH-stat” management of blood gases during cardiopulmonary bypass, involving administration of large amounts of additional carbon dioxide for maintenance of temperature-corrected PaCO2, results in better neurological and cardiac outcome.27
Hypercapnia results in a complex interaction between altered cardiac output, hypoxic pulmonary vasoconstriction, and intrapulmonary shunt, with a net increase in PaO2 (figure).28 Because hypercapnia increases cardiac output, oxygen delivery is increased throughout the body.28 Regional, including mesenteric, blood flow is also increased,29 thereby increasing oxygen delivery to organs. Because hypercapnia (and acidosis) shifts the haemoglobin-oxygen dissociation curve rightwards, and may increase packed-cell volume,30 oxygen delivery to tissues is further increased. Acidosis may reduce cellular respiration and oxygen consumption,31 which may further benefit an imbalance between supply and demand, in addition to greater oxygen delivery. One hypothesis32 is that acidosis protects against continued production of further organic acids (by a negative feedback loop) in tissues, providing a mechanism of cellular metabolic shutdown at times of nutrient shortage—eg, ischaemia.
Acidosis attenuates the following inflammatory processes (figure): leucocyte superoxide formation,33 neuronal apoptosis,34phospholipase A2 activity,35 expression of cell adhesion molecules,36 and neutrophil Na+/H+ exchange.37 In addition, xanthine oxidase (which has a key role in reperfusion injury) is inhibited by hypercapnic acidosis.24 Furthermore, hypercapnia upregulates pulmonary nitric oxide38 and neuronal cyclic nucleotide production,39 both of which are protective in organ injury. Oxygen-derived free radicals are central to the pathogenesis of many types of acute lung injury, and in tissue homogenates, hypercapnia attenuates production of free radicals and decreases lipid peroxidation.19 Thus, during inflammatory responses, hypercapnia or acidosis may tilt the balance towards cell salvage at the tissue level.
However, we know from several case series that human beings, and animals, can tolerate exceptionally high concentrations of carbon dioxide, and when adequately ventilated, can recover rapidly and completely. Therefore, high concentrations (if tolerated) may not necessarily cause harm.
From the published studies reviewed, and from the pathological mechanisms assessed, we postulate that changes in carbon dioxide concentration might affect acute inflammation,33—36 tissue ischaemia,16 ischaemia-reperfusion,2024 and other metabolic,1221,32 or developmental14 processes.
We argue that the recent shift in thinking about hypercapnia must now be extended to therapeutic use of carbon dioxide. Our understanding of the biology of disorders in which hypocapnia is a cardinal element would require fundamental reappraisal if hypocapnia is shown to be independently harmful.
In summary, in critically ill patients, future therapeutic goals involving PaCO2 might be expressed as:“keep the PaCO2 high; if necessary, make it high; and above all, prevent it from being low”.

Effects of a 4-week training with voluntary hypoventilation carried out at low pulmonary volumes

Spennende studie som viser hvordan lav pustefrekvens i selve trening påvirker restitusjonen etterpå. F.eks. hvordan bikarbonat/natron (HCO3-) påvirker melkesyreterskel. Teknikken bestod i å holde pusten 4 sekunder etter utpust, i bolker a 5minutter i løpet av treningsperioden. Det gir spesielt lite oksygen i blodet, som gir mange positive resultater.

Helle studien her:,d.bGE

This study investigated the effects of training with voluntary hypoventilation (VH) at low pulmonary volumes. Two groups of moderately trained runners, one using hypoventilation (HYPO, n = 7) and one control group (CONT, n = 8), were constituted. The training consisted in performing 12 sessions of 55 min within 4 weeks. In each session, HYPO ran 24 min at 70% of maximal O2 consumption (View the MathML source) with a breath holding at functional residual capacity whereas CONT breathed normally. A View the MathML source and a time to exhaustion test (TE) were performed before (PRE) and after (POST) the training period. There was no change in View the MathML source, lactate threshold or TE in both groups at POST vs. PRE. At maximal exercise, blood lactate concentration was lower in CONT after the training period and remained unchanged in HYPO. At 90% of maximal heart rate, in HYPO only, both pH (7.36 ± 0.04 vs. 7.33 ± 0.06; p < 0.05) and bicarbonate concentration (20.4 ± 2.9 mmol L−1 vs. 19.4 ± 3.5; p < 0.05) were higher at POST vs. PRE. The results of this study demonstrate that VH training did not improve endurance performance but could modify the glycolytic metabolism. The reduced exercise-induced blood acidosis in HYPO could be due to an improvement in muscle buffer capacity. This phenomenon may have a significant positive impact on anaerobic performance.

Muscle Pain: Mechanisms and Clinical Significance

En studie til fra Siegfried Mense, om muskelsmerter. Han har ikke fått med seg at trykksensitive nerver kun finnes i huden. Og han har misforstått litt i forskjellene mellom hud-smerter og muskel-smerter siden han sier at hud-smerter ikke kan ha utstrålende effekt. Han har tydeligvis ikke ikke inkludert subcutane nerver i sin vurdering.

Men mye interessant i denne studien likevel. Spesielt vektleggingen av at lav pH er den viktigste bidragsyteren til muskelsmerter.

Han nevner at input fra muskel-nociceptorer har større relevans i ryggmargen enn input fra huden. Derfor er betennelser og lav pH de viktigste drivkreftene i kroniske smerter.

Nevner også at smerter henger sammen, f.eks. at trapezius kan stramme seg for å beskytte brachialis, slik at smerten kjennes i trapezius, mens problemet egentlig sitter i brachialis.

Beskriver også triggerpunkter, men sier at det foreløpig er veldig mange ubesvarte spørsmål om denne teorien.

Muscle pain is a major medical problem: in, the majority (60% to 85%) of the population has had (nonspecific) back pain of muscular origin at some time or other (lifetime prevalence) (1). Pain evoked by myofascial trigger points has a point prevalence of approximately 30% (2). More than 7% of all women aged 70 to 80 years suffer from the fibromyalgia syndrome (e1). In an Italian study, musculoskeletal pain was found to be the most common reason that patients consulted a doctor (3). Thus, treating physicians should be aware of the mechanisms of muscle pain, insofar as they are currently understood.

Subjective differences between muscle pain and cutaneous pain

Muscle pain Cutaneous pain
Electrical nerve stimulation induces only one pain Electrical nerve stimulation induces a first pain and a second pain
Poorly localizable Well-localized
Tearing, cramping, pressing quality Stabbing, burning, cutting quality
Marked tendency toward referral of pain No tendency toward referral of pain
Affective aspect: difficult to tolerate Affective aspect: easier to tolerate

Muscle pain is produced by the activation of specific receptors (so-called nociceptors): these receptors are specialized for the detection of stimuli that are objectively capable of damaging tissue and that are subjectively perceived as painful. They consist of free nerve endings and are connected to the central nervous system (CNS) by way of unmyelinated (group IV) or thinly myelinated (group III) fibers. They can be sensitized and activated by strong mechanical stimuli, such as trauma or mechanical overloading, as well as by endogenous inflammatory mediators including bradykinin (BK), serotonin, and prostaglandin E2 (PGE2).

Two activating chemical substances are particularly important for the generation of muscle pain: adenosine triphosphate (ATP) and protons (H+ ions).

ATP activates muscle nociceptors mainly by binding to the P2X3 receptor molecule, H+ mainly by binding to the receptor molecules TRPV1 (transient receptor potential vanilloid 1) and ASICs (acid-sensing ion channels) (4).

ATP is found in all cells of the body and is released whenever bodily tissues of any type are injured.

A drop in pH is probably one of the main activators of peripheral nociceptors, as many painful disturbances of muscle are associated with low pH in muscle tissue.

Nerve growth factor (NGF) also has a connection to muscle pain: NGF is synthesized in muscle and activates muscle nociceptors (e2). NGF synthesis is increased when a muscle is inflamed (e3).

Acidic tissue pH is one of the main activating factors leading to muscle pain. Practically all pathological and pathophysiological changes of skeletal muscle are accompanied by a drop in pH, among them

  • chronic ischemic states,
  • tonic contractions or spasms,
  • myofascial trigger points,
  • (occupationally induced) postural abnormalities, and
  • myositides.

The neuropeptides stored in muscle nociceptors are released not only when peripheral stimuli activate the nerve endings, but also when spinal nerves are compressed. In this type of neuropathic pain, action potentials are generated at the site of compression and spread not only centripetally, i.e., toward the central nervous system, but also centrifugally, i.e., toward the nociceptive endings, where they induce the release of vasoactive neuropeptides. In this way, neurogenic inflammation comes about, characterized by hyperemia, edema, and the release of inflammatory mediators (8). The inflammatory mediators sensitize the muscle nociceptors and thereby increase neuropathic pain.

The sensitization of the muscle nociceptors by endogenous mediators such as BK and PGE2 is one of the reasons why patients with muscle lesions suffer from tenderness to pressure on the muscle, and from pain on movement or exercise. It is also the reason why many types of muscle pain respond well to the administration of non-steroidal anti-inflammatory drugs (NSAID), which block prostaglandin synthesis.

An influx of nervous impulses from muscle nociceptors into the spinal cord increases the excitability of posterior horn neurons to a greater extent than one from cutaneous nociceptors (9).

Two main mechanisms underlie the overexcitability of spinal nociceptive neurons:

A structural change of ion channels, rendering them more permeable to Na+ and Ca2+, is the short-term result of an influx of nociceptive impulses into the spinal cord. Among other effects, this causes originally ineffective («silent» or «dormant») synapses to become effective.

A change of gene transcription in the neuronal nucleus, leading to a modification of synthetic processes, causes new ion channels to be synthesized and incorporated into the nerve cell membrane. The long-term result of central sensitization is a nociceptive cell whose membrane contains a higher density of ion channels that are also more permeable to ions. This explains the hyperexcitability of the cell. Glial cells, too, particularly microglia, can contribute to the sensitization of central neurons by secreting substances such as tumor necrosis factor a (TNF-a) (8).

The increased excitability of spinal neurons and the spread of excitation within the CNS are the first steps in the process of chronification of muscle pain. The endpoint of chronification consists of structural remodeling processes in the CNS that open up new pathways for nociceptive information and cause pain to persist over the long term. Patients with chronic muscle pain are difficult to treat, because the functional and structural changes in the CNS need time to regress. The fact that not all muscle pain becomes chronic implies that chronification requires not only the mechanisms just discussed, but also other ones, e.g., a genetic predisposition.

Pain arising in muscle is more likely to be referred pain than pain arising in the skin. Referred pain is pain that is felt not (only) at its site of origin, but at another site some distance away. A possible mechanism of referred pain is the spread, within the spinal cord, of excitation due to the muscle lesion (9) (figures 2 and ​and3).3). As soon as the excitation reaches sensory posterior horn neurons that innervate an area beyond the site of the original muscle lesion, the patient feels referred pain in that area, even though none of the nociceptors in it are activated (13).

An example is shown in figure 3: a stimulus delivered to the myofascial trigger point (MTrP) in the soleus muscle causes only mild local pain, while the patient feels more severe (referred) pain in the sacroiliac joint. No conclusive answers are yet available to the questions of why muscle pain is more likely than cutaneous pain to be referred, why it is usually not referred to both proximal and distal sites, and why pain referral is often discontinuous. There is, however, a well-known discontinuity of spinal topography between the C4 and T2 dermatomes.

The main reason why pain arises in muscle spasm is muscle ischemia, which leads to a drop in pH and the release of pain-producing substances such as bradykinin, ATP, and H+.

The vicious-circle concept of muscle spasm – muscle pain causes spasm, which causes more pain, etc. – should now be considered obsolete. Most studies have shown that muscle pain lowers the excitability of the α-motor neurons innervating the painful muscle (14) (a «pain adaptation» model) (15).

Muscle spasm can be precipitated by, among other things, pain in another muscle. Thus, a spasm-like increase EMG activity in the trapezius muscle has been described in response to painful stimulation of the biceps brachii muscle (16). Another source of muscle spasms is pathological changes in a neighboring joint. These sources of pain must be deliberately sought.

In a widespread hypothesis on the origin of MTrP’s (19), it is supposed that a muscular lesion damages the neuromuscular endplate so that it secretes an excessive amount of acetylcholine. The ensuing depolarization of the muscle cell membrane produces a contraction knot that compresses the neighboring capillaries, causing local ischemia. Ischemia, in turn, leads to the release of substances into the tissue that sensitize nociceptors, accounting for the tenderness of MTrP’s to pressure. Substances of this type have been found to be present within the MTrP’s of these patients (20). This supposed mechanism leaves many questions unanswered but is currently the only comprehensive hypothesis on the origin of MTrP’s.

Patients with MTrP’s often have pain in three locations:

  • at the site of the MTrP itself,
  • at the origin or insertion of the affected muscle, because of pulling by the muscle fibers that have been stretched by the contraction knots,
  • and referred pain outside the MTrP (figure 3).

Because the MTrP is cut off from its blood supply by compression of the local microcirculation, oral NSAID’s are not very effective against TrP pain.

Apnea: A new training method in sport?

Veldig viktig studie om hva dykkeres trening i Apnea (å holde pusten) kan bidra med i annen idrett. Bekrefter det meste av det jeg har skrevet om, men oppklarer noe om blodverdier bl.a. Nevner EPO, nyrenes tilpasning, hypoxi, HIF-1, melkesyre, lungevolum

Breath-hold divers have shown reduced blood acidosis, oxidative stress and basal metabolic rate, and increased hematocrit, erythropoietin concentration, hemoglobin mass and lung volumes. We hypothesise that these adaptations contributed to long apnea durations and improve performance. These results suggest that apnea training may be an effective alternative to hypo- baric or normobaric hypoxia to increase aerobic and/or anaerobic performance.

Apnea durations clearly increase with training. Perhaps less well known are the findings that apnea train- ing also increases hematocrit (Hct), erythropoietin (EPO) concen- tration, hemoglobin (Hb) mass, and lung volumes [2–5]. In addition, blood acidosis and oxidative stress were shown to be re- duced after three months of apnea training [6,7]. Therefore, why not encourage apnea training for athletes?

The major determinant of aerobic performance is the capacity to deliver oxygen to the tissues [8]. An increase in the total amount of erythrocytes, as reflected by increased Hct and Hb mass, is med- iated by the glycoprotein hormone EPO, which is predominantly synthesized by the kidneys in response to chronic hypoxia [9] and to some extent (10–15% of total production) by the liver. EPO stimulates the proliferation and maturation of red blood cell precursors in bone marrow, increasing oxygen delivery to muscle and thereby enhancing sports performance [9].

(hypoxic or ischemic conditions) results in a stabilization of the transcription factor hypoxia-inducible factor (HIF)-1a, which increases EPO secretion and the expression of EPO receptor [10].

Furthermore, any training effect vanishes rapidly (two weeks), as the newly formed red cells disappear within a mat- ter of days due to neocytolysis.

The splenic contraction effect

Apnea training may well be a future training method. Splenic contraction has been described in marine mammals as improving oxygen transport, through an increase in circulating erythrocytes. Its consequence is a prolonged dive without injuries. In humans, repeated apneas (five, in general) induce splenic contraction. This increases Hct and Hb (both between 2% and 5%) independently of hemoconcentration [19] and reduces arterial oxygen desaturation, thereby prolonging the apnea duration [3,19–22].

Repeated apneas are known to induce hypoxemia in the spleen and kidney, increas- ing respectively Hct and Hb and serum EPO concentrations [2,23].

First, the splenic contraction develops quickly after three or four apneas separated by two minutes of recovery and is associ- ated with a transient increase in Hb concentration. The amplitude of the spleen volume reduction after repeated apneas, with or without face immersion, varies widely (20–46%) depending on the rate of change in oxygenation [3,19,22,25–27]. The rapidity of the splenic contraction after simulated apneas strongly suggested a centrally-mediated feed-forward mechanism rather than the influ- ence of slower peripheral triggers [19]. These spleen and Hb re- sponses may be trainable.

Second, DeBruijns et al. [2] recently observed that repeated apneas increased EPO concentration by 24%, with the peak value reached 3 h after the last apnea and a return to baseline 2 h later.

The rapid reduction in tissue oxygen levels that oc- curs during apneas has been suggested to stimulate enhanced EPO production [25]. The decreased kidney blood flow induced by apneic vasoconstriction would result in local ischemic hypoxia, stimulating kidney EPO production. Similarly, obstructive sleep ap- nea increases the levels of EPO (􏰀1.6) and Hb (+18%) [24].

The lower SaO2 decrease found in trained divers after repeated apneas may account for the reduced oxygen delivery because of the diving response (bradycardia and vasocon- striction) and/or an increase in oxygen content [1].

Long term-effects

Another important consideration is the persistence of the per- formance gains. Most of the altitude exposure studies reported short-term effects (i.e., weeks). Repeated apneas increase Hct but this increase disappears within 10min after the last apnea [22,26].

The effects of repeated apneas on spleen and endogenous EPO may also constitute an alternative to using rhEPO or its analogues. In addition, comparison of resting Hb mass in elite BHDs and untrained subjects showed a 5% higher Hb mass in the BHDs, and the BHDs also showed a larger relative increase in Hb after three apneas (2.7%). The long-term effect of apnea training on Hb mass might be implicated in elite divers’ performances. Re- cently, it has been found that after a 3-month apnea training pro- gram, the forced expiratory volume in 1 s was higher (4.85 ± 0.78 vs. 4.94 ± 0.81 L, p < 0.05), with concomitant increases in the max- imal oxygen uptake, arterial oxygen saturation, and respiratory compensation point values during an incremental test [30].

In addition to increasing EPO and provoking splenic contraction, apnea training has been hypothesized to modify muscle glycolytic metabolism. An improvement in muscle buffer capacity [6,7,32] would reduce blood acidosis and post-apnea oxidative stress [6]. Delayed acidosis would also be advantageous for exercise perfor- mance. Finally, trained BHDs exhibit high lung volumes [15]. Ap- nea training might be interesting to improve respiratory muscle performance [15], thereby delaying the respiratory muscle fatigue during prolonged and maximal exercise.

Greater cerebral blood flow (CBF) increase was described during long apnea in elite BHDs than in controls and interpreted as a protection of the brain against the alteration of blood gas [33]. The CBF increase observed in BHDs could be the re- sult of an increased capillary density in the brain as has been de- scribed after a prolonged hypobaric hypoxia exposure [35]. These results suggest that apnea training per se provides hypoxic precon- ditioning, increasing hypoxemia and ischemia tolerance [33].

The physiological responses to apnea training exhibited by elite breath-hold divers may contribute to improving sports perfor- mance. These adaptations may be an effective alternative to hypo- baric or normobaric hypoxia to increase performance. Further experimental research of the apnea training effects on aerobic and/or anaerobic performance are needed to confirm this theory.