This energy is expended as the myosin head moves through the power stroke, and at the end of the power stroke, the myosin head is in a low-energy position. After the power stroke, ADP is released; however, the formed cross-bridge is still in place, and actin and myosin are bound together. As long as ATP is available, it readily attaches to myosin, the cross-bridge cycle can recur, and muscle contraction can continue. Note that each thick filament of roughly myosin molecules has multiple myosin heads, and many cross-bridges form and break continuously during muscle contraction.
Multiply this by all of the sarcomeres in one myofibril, all the myofibrils in one muscle fiber, and all of the muscle fibers in one skeletal muscle, and you can understand why so much energy ATP is needed to keep skeletal muscles working.
In fact, it is the loss of ATP that results in the rigor mortis observed soon after someone dies. With no further ATP production possible, there is no ATP available for myosin heads to detach from the actin-binding sites, so the cross-bridges stay in place, causing the rigidity in the skeletal muscles. Relaxing skeletal muscle fibers, and ultimately, the skeletal muscle, begins with the motor neuron, which stops releasing its chemical signal, ACh, into the synapse at the NMJ.
Without the ability to form cross-bridges between the thin and thick filaments, the muscle fiber loses its tension and relaxes. The number and type of skeletal muscle fibers in a given muscle is genetically determined and does not change.
Muscle strength is directly related to the amount of myofibrils and sarcomeres within each fiber. Factors, such as hormones and stress and artificial anabolic steroids , acting on the muscle can increase the production of sarcomeres and myofibrils within the muscle fibers, a change called hypertrophy, which results in an increased mass and bulk of a skeletal muscle. Likewise, decreased use of a skeletal muscle results in atrophy, where the number of sarcomeres and myofibrils decrease but not the number of muscle fibers.
It is common for a limb in a cast to result in dramatically atrophied muscles and certain diseases, such as polio, present with muscular atrophy as a comorbidity. Duchenne muscular dystrophy DMD is a progressive weakening of the skeletal muscles. Over time, as muscle damage accumulates, muscle mass is lost, and greater functional impairments develop. DMD is an inherited disorder caused by an abnormal X chromosome. It primarily affects males, and it is usually diagnosed in early childhood.
DMD usually first appears as difficulty with balance and motion, and then progresses to an inability to walk. ATP supplies the energy for muscle contraction to take place. Muscle contraction does not occur without sufficient amounts of ATP. The amount of ATP stored in muscle is very low, only sufficient to power a few seconds worth of contractions. As it is broken down, ATP must therefore be regenerated and replaced quickly to allow for sustained contraction. There are three mechanisms by which ATP can be regenerated: creatine phosphate metabolism, anaerobic glycolysis, and fermentation and aerobic respiration.
Creatine phosphate is a molecule that can store energy in its phosphate bonds. This acts as an energy reserve that can be used to quickly create more ATP. When the muscle starts to contract and needs energy, creatine phosphate transfers its phosphate back to ADP to form ATP and creatine. This reaction is catalyzed by the enzyme creatine kinase and occurs very quickly; thus, creatine phosphate-derived ATP powers the first few seconds of muscle contraction.
However, creatine phosphate can only provide approximately 15 seconds worth of energy, at which point another energy source has to be used [link]. Glycolysis is an anaerobic non-oxygen-dependent process that breaks down glucose sugar to produce ATP; however, glycolysis cannot generate ATP as quickly as creatine phosphate. Thus, the switch to glycolysis results in a slower rate of ATP availability to the muscle.
The sugar used in glycolysis can be provided by blood glucose or by metabolizing glycogen that is stored in the muscle. The breakdown of one glucose molecule produces two ATP and two molecules of pyruvic acid , which can be used in aerobic respiration or when oxygen levels are low, converted to lactic acid [link] b.
If oxygen is available, pyruvic acid is used in aerobic respiration. However, if oxygen is not available, pyruvic acid is converted to lactic acid , which may contribute to muscle fatigue. This occurs during strenuous exercise when high amounts of energy are needed but oxygen cannot be sufficiently delivered to muscle.
Glycolysis itself cannot be sustained for very long approximately 1 minute of muscle activity , but it is useful in facilitating short bursts of high-intensity output.
This is because glycolysis does not utilize glucose very efficiently, producing a net gain of two ATPs per molecule of glucose, and the end product of lactic acid, which may contribute to muscle fatigue as it accumulates. Aerobic respiration is the breakdown of glucose or other nutrients in the presence of oxygen O 2 to produce carbon dioxide, water, and ATP.
Approximately 95 percent of the ATP required for resting or moderately active muscles is provided by aerobic respiration, which takes place in mitochondria.
The inputs for aerobic respiration include glucose circulating in the bloodstream, pyruvic acid, and fatty acids. Aerobic respiration is much more efficient than anaerobic glycolysis, producing approximately 36 ATPs per molecule of glucose versus four from glycolysis. However, aerobic respiration cannot be sustained without a steady supply of O 2 to the skeletal muscle and is much slower [link] c.
To compensate, muscles store small amount of excess oxygen in proteins call myoglobin, allowing for more efficient muscle contractions and less fatigue. Aerobic training also increases the efficiency of the circulatory system so that O 2 can be supplied to the muscles for longer periods of time.
Muscle fatigue occurs when a muscle can no longer contract in response to signals from the nervous system. The exact causes of muscle fatigue are not fully known, although certain factors have been correlated with the decreased muscle contraction that occurs during fatigue. ATP is needed for normal muscle contraction, and as ATP reserves are reduced, muscle function may decline.
This may be more of a factor in brief, intense muscle output rather than sustained, lower intensity efforts. Lactic acid buildup may lower intracellular pH, affecting enzyme and protein activity. The exact causes of muscle fatigue are not fully known, although certain factors have been correlated with the decreased muscle contraction that occurs during fatigue.
ATP is needed for normal muscle contraction, and as ATP reserves are reduced, muscle function may decline. This may be more of a factor in brief, intense muscle output rather than sustained, lower intensity efforts. Lactic acid buildup may lower intracellular pH, affecting enzyme and protein activity. Intense muscle activity results in an oxygen debt , which is the amount of oxygen needed to compensate for ATP produced without oxygen during muscle contraction.
Oxygen is required to restore ATP and creatine phosphate levels, convert lactic acid to pyruvic acid, and, in the liver, to convert lactic acid into glucose or glycogen.
Other systems used during exercise also require oxygen, and all of these combined processes result in the increased breathing rate that occurs after exercise. Until the oxygen debt has been met, oxygen intake is elevated, even after exercise has stopped.
Relaxing skeletal muscle fibers, and ultimately, the skeletal muscle, begins with the motor neuron, which stops releasing its chemical signal, ACh, into the synapse at the NMJ. Without the ability to form cross-bridges between the thin and thick filaments, the muscle fiber loses its tension and relaxes.
The number of skeletal muscle fibers in a given muscle is genetically determined and does not change. Muscle strength is directly related to the amount of myofibrils and sarcomeres within each fiber.
Factors, such as hormones and stress and artificial anabolic steroids , acting on the muscle can increase the production of sarcomeres and myofibrils within the muscle fibers, a change called hypertrophy, which results in the increased mass and bulk in a skeletal muscle.
Likewise, decreased use of a skeletal muscle results in atrophy, where the number of sarcomeres and myofibrils disappear but not the number of muscle fibers. It is common for a limb in a cast to show atrophied muscles when the cast is removed, and certain diseases, such as polio, show atrophied muscles.
Duchenne muscular dystrophy DMD is a progressive weakening of the skeletal muscles. Over time, as muscle damage accumulates, muscle mass is lost, and greater functional impairments develop.
DMD is an inherited disorder caused by an abnormal X chromosome. It primarily affects males, and it is usually diagnosed in early childhood. This indicates that SOL is activated significantly less than GM in this form of plantar flexion exercise, in accordance with previous studies from our group 5 , 6 , 7 and others 8 , 9 , A meaningful comparison of the physiology and metabolite kinetics of the two muscles requires them to be brought to comparable metabolic state as judged by similar end-exercise PCr depletion and acidification.
This has not previously been reported in comparable detail and was therefore one of the aims of this study. The results presented in particular in Figs 4 and 5 show consistency between the two muscles over the whole range of exercise intensity i. At low activation of the muscle the ATP need is mostly supplied by PCr breakdown and oxidative ATP synthesis, while at high activation there is a large glycolytic contribution, accompanied by acidification.
The relationship between PCr and pH is rather an indirect one. This was consistent between subjects and muscles, and also across the various exercise intensities: during strong exercise the pH dropped much earlier in time than during medium intensity exercise, but always at the same level of PCr depletion.
Figs 4 and 5. This can pose difficulties in comparing or averaging measurements. The near-linear relationship of end-exercise pH and initial L Fig. The correlation of end-exercise pH with end-exercise L Fig. Both linear correlations are steeper for protocol B, which reflects the need for higher L in order to reach the same acidification within a shorter duration of exercise Fig.
It is not our intention here to discuss the implications of these findings for the regulation of glycolysis in exercising muscle. This is still relatively poorly understood in any quantitative way, and although assumptions of the kind used and discussed here can never be entirely either proved or dispensed with the application of high spatiotemporal resolution 31 P MRS to obtain rich datasets in vivo is one of the few obvious ways forward.
Calculated Q max values are broadly within the range of previous reports 4 , 7 , 15 , With protocol A, no significant difference of Q max was found between the two muscles, although measurements using protocol B showed higher values of Q max in SOL.
However, conclusions about differences in Qmax can only, properly, be tentative, considering the quantitative uncertainties even after many years of research in the control relationships between Q and feedback signals like ADP 4. The trend of Q max vs. Much has been made in the 31 P MRS literature of the relationship of Q to [ADP], whose broad characteristics in experiments of this kind is at least consistent with current views of the regulation of oxidative ATP synthesis in skeletal muscle 4.
Figure 3e,f examine this for the first time in detail during the time course of recovery in individual subjects. It may be that the individual variability seen there is evidence that other regulatory mechanisms also contribute 4. The main result of this study regarding ATP synthesis is the confirmation of a fast initial rise of L at stronger muscle activation, with Q rising slower than L. Further to note is the still considerable contribution of L at the end of exercise. The values of L , and particularly more its temporal evolution are not easily accessible.
Most methods use an indirect approach, like VO 2 studies that use whole body oxygen kinetics and power output to make indirect inferences to L. Eqs 5 and 6. On the other hand direct sampling using muscle biopsy is very demanding on the subjects, and limited in temporal resolution and coverage.
The applied quantification from the derivatives of pH and PCr cf. In particular, the method is fundamentally free of assumptions regarding regulation of processes or availability of substrates.
The dissimilarity of the approach to other methods, together with the direct measurement in the cells of a distinct muscle vs. Unlocalized MRS data is often an average over several adjacent muscles, and as a whole body method the VO 2 data is an average over several skeletal muscles plus cardiac and pulmonary contributions. The specificity of spatially averaged data depends on the distribution of the measured effect in the relevant tissue areas, and also on the question of interrogation.
The fast initial rise of L and a slower rise of Q are in line with general assumptions of muscle metabolism at higher activation, and are also confirmed in biopsy studies This is also seen in some VO 2 studies 21 , because the quantified L only contains contribution from the muscles where L is activated. There is a notable difference in later exercise, where in our measurements at higher muscle activation still a strong contribution of L was present, a behavior that was also reported by Conley et al.
The maximum L contribution is much greater in ref. This might also explain the faster decline of PCr contribution in ref. Quantification of Q is expected to be less subject to bias by spatial averaging as the magnitude and especially the temporal evolution of Q is much less dependent on small differences in muscle activation than L , which shows strong change around the lactate-threshold and beyond cf.
The reported temporal evolution of Q throughout exercise and the relation of Q to overall ATP demand in later exercise in ref. This at least supports the applicability of our method of calculating Q via L from temporal derivatives cf.
To the best of our knowledge this is the first report of non-invasive, individual quantification of cytosolic buffer capacity of human muscle. The accurate calculation of buffer capacity demands sufficient temporal resolution of the transient pH rise before the onset of L It therefore has the advantage of providing in vivo buffer capacity values directly in response to exercise.
Literature values of in vivo human muscle buffer capacity, to which our data are consistent, and some of the technical difficulties in measuring and comparing them were discussed at length in ref. There have been relatively few measurements reported since then, and this is still a relatively poorly understood aspect 4.
This is especially so in the less-activated SOL, having smaller initial alkalinization, and thus comparatively bigger influence by noise. The data are included here to demonstrate the feasibility of the method in individuals.
Or better, if possible, by using even higher temporal resolution. This is, to our knowledge, also the first study to report the evolution of proton efflux in recovery, quantified in individual measurements at high temporal resolution and, particularly, making early recovery accessible to a measurement cf. Assessing E is demanding, as it requires good SNR of the fast changing and subsequently declining Pi peak, to accurately quantify pH and its derivative.
At the transition from exercise to recovery many parameters quickly change within the muscle, and the calculations suggest that the effects on the proton efflux from the cell to the blood during early recovery are complicated. E is expected to depend on pH primarily, but there are other relevant factors like the gradient of pH between the cytosol and blood: Low perfusion during times of high proton load can lead to acidification of the surrounding blood, which lowers the pH gradient and therefore restricts E.
Perfusion is known to decrease during recovery, though at higher exercise intensity also a fast initial increase during the first two minutes is reported A significant residual glycolytic contribution would lead to an underestimation of E , as L and E cannot be separated easily.
A residual L during recovery would be expected to decline over time, thus the amount by which E is underestimated would decline as well, emerging as an apparent increase in E. This could potentially explain the initial rise of E in the measurements at medium acidification Fig.
If residual L is present during recovery, it is either downregulated differently in higher acidifying muscles, or another effect is acting to decrease E more strongly. Comprehensive characterization of E in early recovery would greatly benefit from measuring the local muscle perfusion 25 , at a similar time scale.
As a consequence this also supports the estimation of L evolution during exercise, using an E that is modeled by a linear relationship with pH. In early exercise L is calculated without any E, and in later exercise sudden changes of metabolic values are not expected. The model of calculating L in later exercise relies on calculated initial-recovery E , where strong bias can be introduced by averaging. Figure 8a further illustrates the importance of sufficient temporal resolution, which was achieved in our study.
However, there are significant limitations. A more complicated exercise apparatus and protocol would be required to be sure of minimizing variation in muscle fibre recruitment due e. The interactions between contraction and blood flow are complicated and protocol-dependent: we attempted to minimize their effects by acquiring only between the power strokes, but the dynamics of tissue perfusion will still have an influence.
Any study of oxidative ATP synthesis would clearly benefit from measurement of muscle cell oxygenation, e. This study explores subtle details and quick evolutions of metabolic parameters, quantified in individual subjects and muscles, in all metabolic ranges and unprecedented detail.
The necessary high SNR was achieved by using an optimized package consisting of a dedicated rf-coil, efficient localization, and a high magnetic field strength of 7 T.
In summary, the most important findings were:. This was also reflected in quantified levels of glycolysis. The linear correlation of glycolysis to end-exercise pH values suggests that glycolysis is the main factor influencing muscle acidification.
Calculation of glycolytic and oxidative ATP synthesis rates from temporal derivatives of PCr and pH evolution is free of assumptions regarding regulation of processes or availability of substrates. Its successful application in individual non-invasive quantification showed a faster rise of glycolysis than of the oxidative ATP synthesis at higher exercise intensities, in line with VO 2 studies and general assumptions.
Feasibility of fast individual non-invasive quantification of cytosolic buffer capacity was demonstrated, and resulted in reasonable values. In conclusion, the current study presents a concise quantification of many parameters describing skeletal muscle energy metabolism over a wide range of exercise intensities.
A consistent and comprehensive picture of the various stages from the onset of exercise to later stages of recovery is presented, based on localized 31 P MRS measurements in humans. The experimental procedures and protocols were performed in accordance with the Declaration of Helsinki and approved by the Ethics Committee of the Medical University of Vienna.
After an explanation of the purpose, nature and potential risks of the study all subjects gave their written, informed consent prior to the experiments.
Subjects were instructed about the exercise protocol and positioned on the ergometer in the MR scanner. The calf was placed on the form-fitted array coil 27 and fixed in position using a strap across the tibia.
The leg was straight, with the knee extended, similar to a normal standing posture. The setup is described in more detail in ref. Maximum voluntary contraction force MVC was measured by repeated isometric pushing against the locked ergometer pedal. Fifteen subjects were studied voxel positions see Fig. During exercise, two consecutive pedal pushes were performed between each data acquisition. In this form of plantar flexion exercise, with a straight knee and a moderate exercise frequency, predominantly gastrocnemius is expected to be active 29 , and SOL far less.
This was also confirmed by perfusion sensitive MRI, applied in a recent study with the same exercise protocol and setup Typical position of the voxels in soleus and gastrocnemius medialis muscle, respectively, for localized 31 P -MRS at 7 Tesla a.
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