Oxygen regulation and limitation to cellular respiration in mouse skeletal muscle in vivo

Denen Studien sier noe ekstremt viktig: Oksygen, mye eller lite, har ingen ting med regulering av cellerespirasjon å gjøre annet enn å være tilgjengelig som et substrat (altså noe cellene kan leve på). De nevner at oksygen bare blir et problem om det går under 2-3 mmHg. Og at blodceller virker som enn buffer ved at de slipper av oxygen for å holde det ovenfor

Marcinek et.al. 2003. Oxygen regulation and limitation to cellular respiration in mouse skeletal muscle in vivo.


Therefore, we reject a regulatory role for oxygen in cellular respiration and conclude that oxygen acts as a simple substrate for respiration under physiological conditions.

LOW OXYGEN TENSIONS are characteristic of active muscle. During maximal aerobic exercise, intracellular PO2 in skeletal muscle falls to as low as 2–3 mmHg based on an average myoglobin (Mb) saturation of ∼50% (2427). The intracellular oxygen tension at the maximal rate of sustained exercise sets the lower end of the range of physiologically relevant intracellular PO2 values. These values are just above the threshold where isolated mitochondria (12,29), isolated cells (3940), and intact muscle (28) begin to become oxygen limited. Thus the intracellular PO2 reached during heavy muscle exercise may approach the threshold for limiting cellular respiration in vivo.

Experiments in isolated mitochondria and cells have shown that the respiration rate remains relatively constant over the physiological PO2 range (1236), with a clear reduction occurring only at PO2 below 2–3 mmHg.

Our in vivo results from the mouse hindlimb indicate that until a threshold PO2 is reached (2–3 mmHg), there is no effect of oxygen tension on the phosphorylation state of the cell.

In mouse skeletal muscle in vivo, oxygen tension in the physiological range had no significant effect on cellular respiration over a threefold range of baseline rates of oxygen consumption. This is the expected outcome if oxygen is acting as a simple substrate with no significant regulatory role under physiological conditions.

Thus we found no evidence for a change in the relationship between respiration rate and intracellular PO2 with a greater than threefold increase in the fully oxygenated respiration rate. This leads us to conclude that oxygen is not limiting to cellular oxygen consumption and, therefore, does not play a significant role in regulating cellular respiration in vivo under these conditions.

Studies on exercising human muscle support the conclusion that oxygen tension in skeletal muscle does not fall to levels low enough to significantly inhibit cellular respiration except under extreme physiological conditions [i.e., maximum oxygen consumption (V̇O2 max) in trained individuals]. These studies indicate that Mb saturations at the aerobic capacity of human skeletal muscle are ∼50% in vivo (2.4 mmHg) (2427). Our results indicate that above this intracellular PO2, there is little effect of oxygen tension on the cellular respiration rate over the range tested in the present study.

Decreasing the capacity for oxygen delivery by breathing hypoxic air was found to drop Mb saturation below the 50% level and to reduce oxygen consumption during exercise (26). In contrast, supplementing oxygen by breathing of hyperoxic air during a maximum oxygen consumption test either did not effect or resulted in a small increase (∼10%) in V̇O2 max (625).

The transition between oxygen-independent and oxygen-dependent respiration in vivo also occurs in this range of intracellular oxygen tensions (2–3 mmHg). Therefore, an important role of Mb in skeletal muscle may be as an oxygen buffer to help maintain intracellular PO2 above the point at which it becomes limiting to cellular respiration.

In conclusion, the findings of the present study lead us to reject the hypothesis that oxygen plays a regulatory role in cellular respiration over the physiological range of intracellular oxygen tensions. This conclusion is based on the absence of interaction between [PCr], pH (and therefore phosphorylation state), oxygen consumption, and PO2 above 3 mmHg over a greater than threefold range in oxygen consumption rates. These results are consistent with the hypothesis that oxygen acts as a simple substrate for cellular respiration over the physiological range of oxygen tensions.

One-set resistance training elevates energy expenditure for 72 h similar to three sets.

Denen Studien nevner mange interessante ting om Resting Energy Expenditure, altså energien kroppen bruker til å reparere seg etter trening. Vanligvis bruker kroppen 60-75% av energien bare på å opprettholde en fysiologiske funksjoner under hvile, mens i 72t etter trening kan den økes med 6%, eller ca. 420 kJ. Denne studien viste at det var lite ekstra økning om man gjorde en enkelt 15 min økt, eller om man gjorde det 3 ganger.

Heden et.al. 2011. One-set resistance training elevates energy expenditure for 72 h similar to three sets.


Resting energy expenditure (REE) accounts for approximately 60–75% of an individual’s daily energy expenditure (Dolezal and Potteiger 1998Hunter et al. 2000Lemmer et al. 2001Pratley et al. 1994). Determining modalities that increase REE is important as small perturbations in REE can have a significant impact on the regulation and maintenance of body weight (Dolezal and Potteiger 1998Hunter et al. 2000Lemmer et al. 2001Pratley et al. 1994). Unlike aerobic exercise, which results in significant increases in energy expenditure during, and for a short time following cessation of the activity, the energy expenditure during resistance training (RT) is relatively low (Melby et al. 1993Phillips and Ziuraitis 2003), but the increase in energy expenditure after the cessation of the activity and between RT session may be elevated (Dolezal et al. 2000Melby et al. 1993Taaffe et al. 1995).

The REE also corresponds pretty good to the progression of DOMS. But is also, as anything else we have looked at, not correlated to the intensity of DOMS.


Results indicated that both the RT protocols elevated REE by ~ 420 kJ (6%) after 24 h in absolute and relative to fat-free mass and this elevation was maintained in both protocols for 72 h post RT bout.


The results of this investigation support the current ACSM recommendation for RT, which is one set of eight to ten exercises focusing on the major muscle groups (Haskell et al. 2007). Although this recommendation is most often cited for overall muscular fitness, the fact that a single set can elevate REE for 72 h may be an important modality for weight management.


The importance of increasing REE may be with the interaction between REE and energy balance. Increasing REE sufficiently could possibly result in a negative energy balance that could prevent an increase in fat mass.


These factors include elevated body temperature, resynthesis of glycogen from lactate, ion redistribution, replenishment of oxygen stores in blood and muscle, resynthesis of adenosine triphosphate and creatine phosphate, circulation and ventilation, and residual hormone effects (Bahr 1992Bangsbo et al. 1990Borsheim and Bahr 2003). However, it seems that these processes are associated with temporary elevations and do not explain prolonged REE elevations observed beyond 24 h post exercise (Bahr 1992Bangsbo et al. 1990Borsheim and Bahr 2003).


For, example, although not measured in this study, myofibrillar protein turnover (Kim et al. 2005) could increase REE and has been shown to account for as much as 20% of REE (Welle and Nair 1990). In addition, sympathetic nervous system activity may be related to changes in REE. For example, low volume RT has been shown to increase muscle sympathetic nerve activity (Pratley et al. 1994) and to elevate rates of muscle protein synthesis and breakdown up to 48-h post-exercise. Finally, changes in insulin or IGF-1 may contribute to alterations in the repair and resynthesis of skeletal muscle that may contribute to an elevation in REE beyond 24 h (Nindl et al. 2009).

ACE ID genotype affects blood creatine kinase response to eccentric exercise

Hvordan genetiske forskjeller gir økt disponering from CK respons fra trening.


Unaccustomed exercise may cause muscle breakdown with marked increase in serum creatine kinase (CK) activity. The skeletal muscle renin-angiotensin system (RAS) plays an important role in exercise metabolism and tissue injury. A functional insertion (I)/deletion (D) polymorphism in the angiotensin I-converting enzyme (ACE) gene (rs4646994) has been associated with ACE activity. We hypothesized that ACE ID genotype may contribute to the wide variability in individuals’ CK response to a given exercise. Young individuals performed maximal eccentric contractions of the elbow flexor muscles. Pre- and postexercise CK activity was determined. ACE genotype was significantly associated with postexercise CK increase and peak CK activity. Individuals harboring one or more of the I allele had a greater increase and higher peak CK values than individuals with the DD genotype. This response was dose-dependent (mean ± SE U/L: II, 8,882 ± 2,362; ID, 4,454 ± 1,105; DD, 2,937 ± 753, ANOVA, P = 0.02; P = 0.009 for linear trend). Multivariate stepwise regression analysis, which included age, sex, body mass index, and genotype subtypes, revealed that ACE genotype was the most powerful independent determinant of peak CK activity (adjusted odds ratio 1.3, 95% confidence interval 1.03–1.64, P = 0.02). In conclusion, we indicate a positive association of the ACE ID genotype with CK response to strenuous exercise. We suggest that the IIgenotype imposes increased risk for developing muscle damage, whereas the DD genotype may have protective effects. These findings support the role of local RAS in the regulation of exertional muscle injury.

Creatine-Kinase- and Exercise-Related Muscle Damage Implications for Muscle Performance and Recovery

Denne beskriver det aller meste om CK ifh muskelskade under trening. En av få faktorer som korresponderer med DOMS.

Baird et.al. 2012. Creatine-Kinase- and Exercise-Related Muscle Damage Implications for Muscle Performance and Recovery.


However, raised levels of serum CK are still closely associated with cell damage, muscle cell disruption, or disease. These cellular disturbances can cause CK to leak from cells into blood serum [6].

Skeletal cell numbers are established before birth. These cells are designed to last a lifetime and are not subject to turnover and recycling processes that occur in many other cell types. Growth in muscle mass happens in magnitude only (hypertrophy via growth hormone and testosterone). While hypertrophy is readily reversible (atrophy), loss of muscle cell numbers as a result of damage would be progressively more serious.

Unaccustomed exercise, particularly eccentric muscle contractions, initiates mechanical muscle damage of varying degrees [8]. Metabolic muscle disturbance is thought to result in release of cellular components through a cascade of events, which begin with depletion of ATP and result in the leakage of extracellular calcium ions into intracellular space, due to both Na-K-ATPase and Ca2+-ATPase pump dysfunction. Intracellular proteolytic enzyme activity can increase and promote muscle protein degradation and augmented cell permeability, which allows some cell contents to leak into the circulation [910].

Some individuals are found to have high levels of serum CK compared to other similar individuals when exposed to the same exercise protocol (including moderate exercise) even when main comparability factors such as gender, age, and training status are accounted for in data analysis. In some cases, this variability may indicate an underlying myosis, but in many other cases the cause is unknown [7].

Base levels of serum CK in general populations are variable 35–175 U/L [16] with ranges from 20 to 16,000 U/L, and this wide range reflects the inconsistent occurrence of subclinical disorders and minor injury, genetic factors, physical activity status, and medication [17].

In examples of rhabdomyolysis (clinically diagnosed muscle damage) CK levels have been found at 10,000–200,000 U/L and as high as 3×106 U/L [18]. Such levels clearly signal strong disturbance or disintegration of striated muscle tissue with concomitant leakage of intracellular muscle constituents into the circulation. In the absence of specific myocardial or brain infarction, physical trauma, or disease, serum CK levels greater than 5,000 U/L are generally considered to indicate serious disturbance to muscle [10].

It has been proposed that higher than normal levels of tissue CK activity may augment the availability of cellular energy and improve myofibril contraction responses [21].

Serum CK levels alone may not provide a fully accurate reflection of structural damage to muscle cells [2223]. Some studies have reported that serum CK levels were affected by hydration status prior to eccentric exercise and varied within subject groups of comparable male volunteers, whilst muscle biopsies revealed similar ultrastructure damage to Z-band muscle fibres. Muscle soreness did not differ between groups [24].

Considering the significant increase in CK levels which have been found as a result of high-intensity exercise compared to lower intensity [2930], the decrements in performance experienced [2931], and higher levels of PGE2 reported [33] even when exercise volume is standardised suggests that higher-intensity exercise will cause the greater disruption of cell membranes; however, with adequate recovery, it may also elicit the greatest adaptations to exercise in the shortest time.

When activities occur that deplete ATP levels, such as physical exercise, glucose depletion, or hypoxia, AMPK is activated. When activated, it in turn stimulates a range of physiological and biochemical processes and pathways that increase ATP production and at the same time switch off pathways that involve ATP consumption. Recent work has shown a strong correlation between a sedentary lifestyle, inactive AMPK, and morbidity diseases such as metabolic syndrome, type 2 diabetes, and dementia [56].

The role of CK in energy management is maintenance of PCr levels to provide an immediate energy supply in the first few seconds of physical activity. It is likely that AMPK has a role in controlling CK activity, and some work has demonstrated that AMPK may regulate CK and is sensitive to the Cr : PCr ratio and that increased creatine levels stimulate AMPK activity [57].

For example eccentrically biased exercise (e.g., downhill running) will elicit greater postexercise levels of serum CK than equivalent concentrically biased exercise (e.g., uphill running) though the former is less energy metabolism demanding than the latter [41]. This highlights the integrated complexity of metabolism and mechanical damage as eccentric-biased exercise is associated with increased indices of muscle damage (i.e., DOMS) which is mainly a result of micro-damage within the myocyte [5960].

ATP levels never deplete to critical levels; this is because the sensitivity of ATP is set very high to guarantee that they never deplete, so a slight reduction in high ATP level triggers an early protective reaction.

Exercise modality can affect the appearance of CK in blood serum. Eccentric resistance training CK serum levels can peak between 72 hrs [3145] and 96 hrs [67] to 120 hrs [4] (see Figure 3(b)). Training status may affect this time response. Full body eccentric resistance training in resistance trained (RT) and untrained (UT) men elicited a significant (UT 𝑃=0.002, RT 𝑃=0.02) increase in CK serum levels at 24 hrs. This signified the peak response in the RT group, whilst levels in the UT group continued to rise and peaked at 72 hrs [68]. However, three sets of 50 maximal eccentric leg flexion contractions in untrained men resulted in a significant (𝑃<0.05) increase in CK serum levels at 24 hrs; levels decreased over the next 2 days followed by a nonsignificant (𝑃>0.05) increase at 96 hr [23], and 10 sets of 10 reps of 70% body mass barbell squats incorporating eccentric and concentric contractions in non-resistance-trained males and females resulted in a peak serum CK response at 24 hr after exercise. A series of plyometric jumps performed over 2–5 minutes by untrained men produced a peak CK serum response at 48 hrs [69], and 90 minutes of endurance cycle ergometer exercise at a set absolute workload (1.5 kilo ponds at 60 revolutions per minute) performed by untrained men three days consecutively caused a significant (𝑃<0.05) increase in serum CK levels 3 hours after the first exercise session and peak CK serum levels occurred immediately after the third day of exercise, 72 hrs from the initiation of exercise [6] (see Figure 3(a)). Stepping exercise resulted in a CK serum increase in women at day 3, whereas, there was no significant increase in CK serum levels in men performing the same protocol (see Figure 3(c)).

Changes in inflammatory mediators following eccentric exercise of the elbow flexors.

Nevner hvordan forskjellige inflammasjonsmarkører ikke stemmer nevneverdig godt overens med progresjonen av stølhet. Den nevner også noe veldig interessant om at det er IL-10, som er en anti-inflammatorisk cytokin, som gjør at vi tilpasses treningen siden den øker betraktelig ved «repeated bouts of training».

(Hirose et.al. 2004) http://www.ncbi.nlm.nih.gov/pubmed/15633588


The aims of this study were to examine the plasma concentrations of inflammatory mediators including cytokines induced by a single bout of eccentric exercise and again 4 weeks later by a second bout of eccentric exercise of the same muscle group. Ten untrained male subjects performed two bouts of the eccentric exercise involving the elbow flexors (6 sets of 5 repetitions) separated by four weeks. Changes in muscle soreness, swelling, and function following exercise were compared between the bouts. Blood was sampled before, immediately after, 1 h, 3 h, 6 h, 24 h (1 d), 48 h (2 d), 72 h (3 d), 96 h (4 d) following exercise bout to measure plasma creatine kinase (CK) activity, plasma concentrations of myoglobin (Mb), interleukin (IL)-1beta, IL-1 receptor antagonist (IL-1ra), IL-4, IL-6, IL-8, IL-10, IL-12p40, tumor necrosis factor (TNF)-alpha, granulocyte colony-stimulating factor (G-CSF), myeloperoxidase (MPO), prostaglandin E2 (PGE2), heat shock protein (HSP) 60 and 70. After the first bout, muscle soreness increased significantly, and there was also significant increase in upper arm circumference; muscle function decreased and plasma CK activity and Mb concentration increased significantly. These changes were significantly smaller after the second bout compared to the first bout, indicating muscle adaptation to the repeated bouts of the eccentric exercise. Despite the evidence of greater muscle damage after the first bout, the changes in cytokines and other inflammatory mediators were quite minor, and considerably smaller than that following endurance exercise. These results suggest that eccentric exercise-induced muscle damage is not associated with the significant release of cytokines into the systemic circulation. After the first bout, plasma G-CSF concentration showed a small but significant increase, whereas TNF-alpha and IL-8 showed significant decreases compared to the pre-exercise values. After the second bout, there was a significant increase in IL-10, and a significant decrease in IL-8. In conclusion, although there was evidence of severe muscle damage after the eccentric exercise, this muscle damage was not accompanied by any large changes in plasma cytokine concentrations. The minor changes in systemic cytokine concentration found in this study might reflect more rapid clearance from the circulation, or a lack of any significant metabolic or oxidative demands during this particular mode of exercise. In relation to the adaptation to the muscle damage, the anti-inflammatory cytokine IL-10 might work as one of the underlying mechanisms of action.

Central and Peripheral Fatigue in Male Cyclists after 4-, 20-, and 40-km Time Trials.

Nevner at «central fatigue» kommer av lavt oksygennivå, spesielt etter lange treningsøkter. «Peripheral fatigue» kommer etter korte og intense treningøkter.


Time to complete 4 km, 20 km and 40 km was 6.0±0.2 min, 31.8±1.0 min and 65.8±2.2 min, at average exercise intensities of 96%, 92% and 87% of VO2max, respectively.

Greater peripheral fatigue was evident after the 4 km (40% reduction in potentiated twitch) compared to the 20 km (31%) and 40 km TTs (29%). In contrast, longer TTs were characterized by more central fatigue, with greater reductions in voluntary activation measured by motor nerve (-11% and -10% for 20 km and 40 km vs. -7% for 4 km) and cortical (-12% and -10% for 20 km and 40 km vs. -6% for 4 km) stimulation.


These data demonstrate fatigue after self-paced exercise is task-dependent, with a greater degree of peripheral fatigue after shorter, higher intensity (∼6 min) TTs and more central fatigue after longer, lower intensity TTs (>30 min).

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: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4127040/


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].