Exercise-induced muscle injury in humans frequently occurs after unaccustomed exercise, particularly if the exercise involves a large amount of eccentric (muscle lengthening) contractions. Direct measures of exercise-induced muscle damage include cellular and subcellular disturbances, particularly Z-line streaming. Several indirectly assessed markers of muscle damage after exercise include increases in T2 signal intensity via magnetic resonance imaging techniques, prolonged decreases in force production measured during both voluntary and electrically stimulated contractions (particularly at low stimulation frequencies), increases in inflammatory markers both within the injured muscle and in the blood, increased appearance of muscle proteins in the blood, and muscular soreness. Although the exact mechanisms to explain these changes have not been delineated, the initial injury is ascribed to mechanical disruption of the fiber, and subsequent damage is linked to inflammatory processes and to changes in excitation-contraction coupling within the muscle. Performance of one bout of eccentric exercise induces an adaptation such that the muscle is less vulnerable to a subsequent bout of eccentric exercise. Although several theories have been proposed to explain this "repeated bout effect," including altered motor unit recruitment, an increase in sarcomeres in series, a blunted inflammatory response, and a reduction in stress-susceptible fibers, there is no general agreement as to its cause. In addition, there is controversy concerning the presence of sex differences in the response of muscle to damage-inducing exercise. In contrast to the animal literature, which clearly shows that females experience less damage than males, research using human studies suggests that there is either no difference between men and women or that women are more prone to exercise-induced muscle damage than are men.

Exercise-induced muscle damage in humans.

A strong relationship between aerobic fitness and the aerobic response to repeated bouts of high intensity exercise has been established, suggesting that aerobic fitness is important in determining the magnitude of the oxidative response. The elevation of exercise oxygen consumption (VO2) is at least partially responsible for the larger fast component of excess post-exercise oxygen consumption (EPOC) seen in endurance-trained athletes following intense intermittent exercise. Replenishment of phosphocreatine (PCr) has been linked to both fast EPOC and power recovery in repeated efforts. Although 31P magnetic resonance spectroscopy studies appear to support a relationship between endurance training and PCr recovery following both submaximal work and repeated bouts of moderate intensity exercise, PCr resynthesis following single bouts of high intensity effort does not always correlate well with maximal oxygen consumption (VO2max). It appears that intense exercise involving larger muscle mass displays a stronger relationship between VO2max and PCr resynthesis than does intense exercise utilising small muscle mass. A strong relationship between power recovery and endurance fitness, as measured by the percentage VO2max corresponding to a blood lactate concentration of 4 mmol/L, has been demonstrated. The results from most studies examining power recovery and VO2max seem to suggest that endurance training and/or a higher VO2max results in superior power recovery across repeated bouts of high intensity intermittent exercise. Some studies have supported an association between aerobic fitness and lactate removal following high intensity exercise, whereas others have failed to confirm an association. Unfortunately, all studies have relied on measurements of blood lactate to reflect muscle lactate clearance, and different mathematical methods have been used for assessing blood lactate clearance, which may compromise conclusions on lactate removal. In summary, the literature suggests that aerobic fitness enhances recovery from high intensity intermittent exercise through increased aerobic response, improved lactate removal and enhanced PCr regeneration.

The relationship between aerobic fitness and recovery from high intensity intermittent exercise.

The activity patterns of many sports (e.g. badminton, basketball, soccer and squash) are intermittent in nature, consisting of repeated bouts of brief (≤6-second) maximal/near-maximal work interspersed with relatively short (≤60-second) moderate/low-intensity recovery periods. Although this is a general description of the complex activity patterns experienced in such events, it currently provides the best means of directly assessing the physiological response to this type of exercise. During a single short (5- to 6-second) sprint, adenosine triphosphate (ATP) is resynthesised predominantly from anaerobic sources (phosphocreatine [PCr] degradation and glycolysis), with a small (<10%) contribution from aerobic metabolism. During recovery, oxygen uptake (V-dotO2) remains elevated to restore homeostasis via processes such as the replenishment of tissue oxygen stores, the resynthesis of PCr, the metabolism of lactate, and the removal of accumulated intracellular inorganic phosphate (Pi). If recovery periods are relatively short, V-dotO2 remains elevated prior to subsequent sprints and the aerobic contribution to ATP resynthesis increases. However, if the duration of the recovery periods is insufficient to restore the metabolic environment to resting conditions, performance during successive work bouts may be compromised. Although the precise mechanisms of fatigue during multiple sprint work are difficult to elucidate, evidence points to a lack of available PCr and an accumulation of intracellular Pi as the most likely causes. Moreover, the fact that both PCr resynthesis and the removal of accumulated intracellular Pi are oxygen-dependent processes has led several authors to propose a link between aerobic fitness and fatigue during multiple sprint work. However, whilst the theoretical basis for such a relationship is compelling, corroborative research is far from substantive. Despite years of investigation, limitations in analytical techniques combined with methodological differences between studies have left many issues regarding the physiological response to multiple sprint work unresolved. As such, multiple sprint work provides a rich area for future applied sports science research.

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Multiple sprint work : physiological responses, mechanisms of fatigue and the influence of aerobic fitness.

Chronic obstructive pulmonary disease (COPD) is a major health care problem. Formerly mainly a disease of men, women are increasingly frequently afflicted. In many of these patients, exercise intolerance is the chief complaint. Few effective therapies are available. In recent years, dysfunction of the muscles of ambulation has been identified as a source of a portion of the exercise intolerance these patients experience, and this dysfunction has been shown to be, at least in part, remediable. Mechanisms inducing muscle dysfunction include disuse atrophy, malnutrition, low levels of anabolic steroids, and myopathy from corticosteroid use. Endurance exercise training has been conclusively demonstrated to improve exercise tolerance in COPD. Recent studies suggest that strength training is beneficial as well. A new frontier of therapy for muscle dysfunction in COPD is the use of anabolic hormones. Testosterone supplementation has been shown to increase muscle mass and strength in both hypogonadal and eugonadal healthy men. Low-dose testosterone supplementation is being considered for use in postmenopausal women. Though short-term administration of testosterone in moderate doses seems to be well tolerated in both men and women, further studies are required before safety and effectiveness can be established for routine use in COPD patients.

Skeletal muscle dysfunction in chronic obstructive pulmonary disease: A statement of the American Thoracic Society and European Respiratory Society

31P MRS offers a unique view of muscle metabolism in vivo, but correct quantification is important. Inter-study correlation of estimates of [Pi] and [phosphocreatine (PCr)] in a number of published studies suggest that the main technical problem in calibrated 31P MRS studies is the measurement of PCr and Pi signal intensities, rather than absolute quantification of [ATP]. For comparison, we discuss the few published biopsy studies of calf muscle and a selection of the many studies of quadriceps muscle. The ATP concentration is close to the value that we obtained in calf muscle in our own study, presented here, on four healthy subjects, by localised 31P MRS using a surface coil incorporating an internal reference and calibrated using an external phantom. However, the freeze-clamp biopsy PCr concentration is approximately 20% lower than the value obtained by 31P MRS, consistent with PCr breakdown by creatine kinase during freezing. Finally, we illustrate some consequences of uncertainty in resting [PCr] for analysis of mitochondrial function from PCr kinetics using a published 31P MRS study of exercise and recovery: the lower the assumed resting [PCr], the lower the absolute rate of oxidative ATP synthesis estimated from the PCr resynthesis rate; in addition, the lower the assumed resting [PCr], or the higher the assumed [total creatine], the higher the apparent resting [ADP], and therefore the more sigmoid the relationship between the rate of oxidative ATP synthesis and [ADP]. Correct quantification of resting metabolite concentrations is crucially important for this sort of analysis. Our own results ([PCr] = 33 +/- 2 mM, [Pi] = 4.5 +/- 0.2 mM, and [ATP] = 8.2 +/- 0.4 mM; mean +/- SEM) are close to the overall mean values of the 10 published studies on calf muscle by 'calibrated' 31P MRS (as in the present work), and of [PCr] and [Pi] in a representative selection of 'uncalibrated' 31P MRS studies (i.e. from measured PCr/ATP and Pi/ATP ratios, assuming a literature value for [ATP]).

Absolute quantification of phosphorus metabolite concentrations in human muscle in vivo by 31P MRS: a quantitative review

We examined the effect of differences in exercise intensity on the time constant (tc) of phosphocreatine (PCr) resynthesis after exercise and the relationships between tc and maximal oxygen uptake (VO2max) in endurance-trained runners (n = 5) and untrained controls (n = 7) (average VO2max = 66.2 and 52.0 ml.min-1.kg-1, respectively). To measure the metabolism of the quadriceps muscle using phosphorus nuclear magnetic resonance spectroscopy, we developed a device which allowed knee extension exercise inside a magnet. All the subjects performed four types of exercise: light, moderate, severe and exhausting. The end-exercise PCr: [PCr+inorganic phosphate (P(i))] ratio decreased significantly with the increase in the exercise intensity (P < 0.01). Although there was little difference in the end-exercise pH, adenosine diphosphate concentration ([ADP]) and the lowest intracellular pH during recovery between light and moderate exercise, significant changes were found at the two higher intensities (P < 0.01). These changes for runners were smaller than those for the controls (P < 0.05). The tc remained constant after light and moderate exercise and then lengthened in proportion to the increase in intensity (P < 0.05). The runners had a lower tc at the same PCr and pH than the controls, particularly at the higher intensity (P < 0.05). There was a significant correlation between tc and [ADP] in light exercise and between tc and both end-exercise PCr and pH in severe and exhausting exercise (P < 0.05). The threshold of changes in pH and tc was a PCr: (PCr+P(i)) ratio of 0.5. There was a significant negative correlation between the VO2max and tc after all levels of exercise (P < 0.05). However, in the controls a significant correlation was found in only light and moderate exercise (P < 0.05). These findings suggest the validity of the use of tc at an end-exercise PCr: (PCr+P(i)) ratio of more than 0.5 as a stable index of muscle oxidative capacity and the correlation between local and general aerobic capacity. Moreover, endurance-trained runners are characterized by the faster PCr resynthesis at the same PCr and intracellular pH.

Control of the rate of phosphocreatine resynthesis after exercise in trained and untrained human quadriceps muscles

To investigate the time-course of changes in transverse relaxation time (T2) and cross-sectional area (CSA) of the quadriceps muscle after a single session of eccentric exercise, magnetic resonance imaging was performed on six healthy male volunteers before and at 0, 7, 15, 20, 30 and 60 min and 12, 24, 36, 48, 72 and 168 h after exercise. Although there was almost no muscle soreness immediately after exercise, it started to increase 1 day after, peaking 1–2 days after the exercise (P<0.01). Immediately after exercise, T2 increased significantly in the rectus femoris, vastus lateralis and intermedius muscles (P<0.05) and decreased quickly continuing until 60 min after exercise. At and after the 12th h, a significant increase was perceived again in the T2 values of the vastus lateralis and intermedius muscles (P<0.01) [maximum 9.3 (SEM 2.8)% and 10.9 (SEM 2.2)%, respectively]. The maximal values were exhibited at 24–36 h after exercise. In contrast, the rectus femoris muscle showed no delayed-stage increase. Also, in CSA, an increase after 12 h was observed in addition to the one immediately after exercise in the vastus lateralis, intermedius and medialis and quadriceps muscles as a whole (P < 0.01), reaching the maximal values at 12–24 h after exercise. The plasma creative kinase activity remained unchanged up to 24 h after and then increased significantly 48 h after exercise (P < 0.05). Beginning 12 h after exercise, the subjects whose T2 and CSA increased less than the others displayed a faster decrease in muscle soreness. These results suggested that T2 and CSA displayed bimodal responses after eccentric exercise and the time-courses of changes in them were similar to those in muscle soreness.

Changes in magnetic resonance images in human skeletal muscle after eccentric exercise

We attempted to determine the change in total excess volume of CO2 output (CO2 excess) due to bicarbonate buffering of lactic acid produced in exercise due to endurance training for approximately 2 months and to assess the relationship between the changes of CO2 excess and distance-running performance. Six male endurance runners, aged 19-22 years, were subjects. Maximal oxygen uptake (VO2max), oxygen uptake (VO2) at anaerobic threshold (AT), CO2 excess and blood lactate concentration were measured during incremental exercise on a cycle ergometer and 12-min exhausting running performance (12-min ERP) was also measured on the track before and after endurance training. The absolute magnitudes in the improvement due to training for CO2 excess per unit of body mass per unit of blood lactate accumulation (delta la-) in exercise (CO2 excess.mass-1.delta la-), 12-min ERP, VO2 at AT (AT-VO2) and VO2max on average were 0.8 ml.kg-1.l-1.mmol-1, 97.8 m, 4.4 ml.kg-1. min-1 and 7.3 ml.kg-1.min-1, respectively. The percentage change in CO2 excess.mass-1.delta la- (15.7%) was almost same as those of VO2max (13.7%) and AT-VO2 (13.2%). It was found to be a high correlation between the absolute amount of change in CO2 excess.mass-1.delta la-, and the absolute amount of change in AT-VO2 (r = 0.94, P less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of endurance training on excessive CO2 expiration due to lactate production in exercise

Four well-trained combination skiers were studied through pre- and post-training for the effects of short-term intermittent training during hypoxia on muscle energetics during submaximal exercise as measured by Phosphorus-31 nuclear magnetic resonance and maximal aerobic power (
 
$$\dot V$$

 O2max). The hypoxia and training in the cold was conducted in a hypobaric chamber and comprised 60-min aerobic exercise (at an intensity equivalent to the blood lactate threshold), using a cycle ergometer or a treadmill twice a day for 4, consecutive days at 5°C, in conditions equivalent to an altitude of 2000 m (593 mm Hg). No change in 
$$\dot V$$

 O2max was observed over the training period, while in the muscle energetics during submaximal exercise, the values of phosphocreatine/(phosphocreatine + inorganic phosphate) and intracellular pH were found to be significantly increased by training during hypoxia. During recovery, the time constant of phosphocreatine was found to have been significantly reduced [pre, 27.9 (SD 6.7) s; post, 22.5 (SD 4.7) s, P < 0.01]. The observed inhibition of phosphocreatine as well as that of intracellular pH changes after training during hypoxia and quicker recovery of phosphocreatine in submaximal exercise tests, may indicate improved oxidative capacity (i.e. a high adenosine 5′-triphosphate formation rate) despite the short-term hypoxia training.

Mitsuharu Inaki

Papers

Control of the rate of phosphocreatine resynthesis after exercise in trained and untrained human quadriceps muscles

Changes in magnetic resonance images in human skeletal muscle after eccentric exercise

Effect of endurance training on excessive CO2 expiration due to lactate production in exercise

Muscle energetics in short-term training during hypoxia in elite combination skiers

Index of the oxidative potential in human quadriceps muscle: simultaneous measurements of [31P]NMR and oxygen consumption during exercise.