Actu Physiol S c u d 1992, 146, 11-14
Bio-energetic changes in human gastrocnemius muscle 1-2 days after strenuous exercise G. J. K E M P , D . J. T A Y L O R , G. K. R A D D A and B. R A J A G O P A L A N MRC Clinical and Biochemical Magnetic Resonance Unit, John Radcliffe Hospital, Oxford, UK KEMP, G. J., TAYLOR, D. J., RADDA,G. K. & RAJAGOPALAN, B. 1992. Bio-energetic changes in human gastrocnemius muscle 1-2 days after strenuous exercise. Actu Phj/siul Scand 146, 11-14. Received 14 January 1992, accepted 4 April 1992. ISSN 00016772. MRC Clinical and Biochemical Magnetic Resonance Unit, John Radcliffe Hospital, Oxford, UK. [31P]magnetic resonance spectroscopy was used to study the metabolic sequelae of intense muscular activity in gastrocnemius of seven subjects 1-2 days after a 67-mile bicycle ride. The muscle was examined at rest, during a test exercise and during recovery from test exercise. Post-ride and pre-ride results were compared. At rest, the ratio of phosphocreatine to ATP (PCr/ATP) was increased post-ride; during test exercise PCr/(PCr+Pi) was lower post-ride; and the recoveries of PCr, Pi and PCr/(PCr Pi) after test exercise were delayed, with decreased ‘overshoot’ of PCr/(PCr+Pi) (which is due to recovery of Pi to below its resting value). Mild mitochondria1 damage (perhaps due to exposure to high cytosolic [Pi] during the bicycle ride) may explain some of these results. In contrast to reports of largely eccentric exercise there was no increase in resting Pi/ATP. We have thus demonstrated perturbations of muscle bio-energetics 1-2 days after strenuous exercise, in the absence of convincing enzymological evidence of muscle damage.
+
Key words: magnetic resonance spectroscopy, exercise, muscle, mitochondria, fatigue, recovery from exercise.
Phosphorus magnetic resonance spectroscopy ([31P]MRS) has been used to detect pathological abnormalities of mitochondrial or glycolytic function in skeletal muscle (Radda et al. 1989) and to demonstrate bio-energetic changes after physical training (McCully et al. 1989) and in fatigue (Newham & Cady 1990). Previous MRS studies have shown high intramuscular phosphate (Pi) concentration persisting for at least 2 days after eccentric and perhaps other exercise (McCully et al. 1988, Newham & Cady 1990). We have used [31P]MRS to investigate the effects of a single bout of prolonged intense muscular activity (a 67-mile bicycle ride) on the bioenergetics of untrained gastrocnemius muscle. Correspondence: Dr G. J. Kernp, MRC Clinical and Biochemical Magnetic Resonance Unit, John Radcliffe Hospital, Headington, Oxford OX3 9DU, UK.
At 1-2 days we found changes in the muscle at rest and in response to test exercise which suggest that MRS can detect minor muscle damage in the absence of appreciable change in plasma ‘muscle’ enzymes. A preliminary account of this work has been presented (Kemp et al. 1991). MATERIALS AND METHODS Seven healthy untrained adults (22-34 years; one male and six female) who undertook a 67-mile bicycle ride for charity were studied by MRS the day before, and either 1 day (four subjects) or 2 days (four subjects), after the ride (for logistic reasons all postride studies could not be carried out on the same day, but no differences were observed between subjects studied 1 and 2 days after the ride). [31P]MR spectra of the right gastrocnemius muscle were obtained from the supine subject as described previously (Hands et al. 1986), using a 6 cm two-turn
11
12
G.3. Kemp
et al.
Table 1. Results of gastrocnemius exercise before and after bicycle ride (mean fSD) Measurement Rest
Mean difference over whole of exercise End of exercise Recovery halftime (s)
Pre-ride Cytosolic pH PCr/ATP Pi/i\TP [ADP] (pmol I-’) PCr/(PCr Pi) PH [ADP] @mol I-’) PCr/(PCr Pi) PH [ADP] (jimol 1 I ) of PCr of Pi of PCr/(PCr Pi) of .4DP at 0.9 min over 2-10 min
+
+
+
Per cent recovery of PCr/(PCr + Pi) Plasmd e n q mes Creatine kinase ’4spartate amino transferase
7.02 f 0.02 2.4 fO.l 0.32 k 0.05 23+4
0.46 k 0.13 6.83i0.19 72f31 2 0 i 11 20f5 19k8 8i3 107 F 14 117k6 Reference range 21--195 15-42
Post-ride 7.02 & 0.02 2.6 0.2 0.31 k 0.08 17k4 - 0.06 i0.03 - 0.03 0.04 4f20 0.40 & 0.12 6.77k0.13 85 2 23 23+8 24+5 24+7 10k4 93+ll 107 2 Post-ride 240+ 133 35 f 15
+
P ns. 0.0003 ns. ns. 0.01 n.s.
ns. n.s. ns. n.s. 0.03 0.02 0.01 n.s. 0.01 0.002 results (range 96-111) (range 13-55)
‘Pre-ride’ and ‘post-ride’ refer to data obtained before and 1-2 days after the bicycle ride. ‘Mean difference over whole exercise’ is the overall mean of the average differences between values at matched time points during test exercise (i.e. post- minus pre-ride, averaged over the whole of exercise for each subject). Plasma enzymes were only obtained post-ride and are compared with the laboratory reference range. Data are compared by paired t-test
surface coil in a 1.9 Tesla superconducting magnet (Oxford Magnet Technologj-, Oxford, UK) interfaced to a Bruker spectrometer (Bruker, Coventry, UK). Pulse-length was 80 p s and interpulse delay 2 s (90’ pulse at coil-centre was 140 ps). Peak areas of Pi, PCi and P-ATP were measured by manual triangulation, pH was calculated from the chemical shift of Pi (Arnold et al. 1985) and since the reaction catalysed by creatine kinase is at equilibrium, free (ADP) was calculated from PCr/ATP and pH (Arnold et al. 1985). The subjects exercised by depressing a pedal at a rate of 30 min-’. The initial load was set at 100,b of lean body mass (Hands et al. 1986) for 5 min, increasing incrementally by 6 o,, of lean body mass each 1.25 min for a total of up to 15 min. Spectra were obtained during 10 min of recovery and recovery halftimes were estimated by interpolation using plots of fractional recover). against time. Creatine kinase and aspartate aminotransferase were measured on plasma samples obtained at the time of the post-ride study by standard methods on a Technicon RAlOOO analyser (Technicon, Basingstoke, UK) . Data are presented as mean SD, and differences are analysed by paired t-test.
+
RESULTS In resting muscle, compared to pre-ride data (Table l), PCr/ATP was increased by 10% post-ride. There were no other significant differences. Figure 1a, b & c shows the pre- and (2 days) post-ride responses to the test exercise in one subject: results from all were similar but in overall mean data (not shown) between-subject variation obscures the pre-post difference. Calculated over the whole of exercise for each subject, mean p H and PCr/(PCr Pi) were lower post-ride (Table l), while the ADP response did not differ significantly. Figure I d shows the recovery of PCr/ (PCr + Pi) after test exercise in a single subject. In all subjects the recovery half-times of [Pi], [PCr] and PCr/(PCr + Pi) were increased postride compared to pre-ride (Table 1). Pre-ride, PCr/(PCr+ Pi) recovered to 100% at 0.75 min and reached a stable value of 120% from 2-10 min; post-ride, it reached lOOyo only at
+
Muscle changes after strenuous exercise 7.101
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Minutes of exercise
Minutes of exercise
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125 100 75
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1
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10
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Minutes of recovery
Figure 1. [31P]MRSdata from gastrocnemius muscle in one representativefemale subject during test exercise (0, pre-ride; 0 , 2 days post-ride) showing response of ( a ) PCr/(PCr Pi), which is an index of phosphocreatine concentration,(b) cytosolic pH and (c) calculated [ADP] during test exercise and ( d ) percentage recovery of PCr/(PCr Pi) after test exercise.
+
+
1.4 min and achieved a stable value of only 108%. The 'overshoot' to more than lOOyo is real: mean recovery from 2-10 min was greater than lOOyo (at least P < 0.05) in all but one subject, pre- and post-ride; the overall means from 2 to 10 min were greater than 100yo,preand post-ride; and this value was greater prethan post-ride (Table 1). Post-ride creatine kinase was above the reference range in three subjects, aspartate aminotransferase in three subjects and both enzymes in only two subjects (Table 1). DISCUSSION Resting PCr/ATP was slightly raised in gastrocnemius 1-2 days after a 67-mile bicycle ride. PCr is in equilibrium (Arnold et al. 1985) with creatine (which is influenced by creatine uptake), cytosolic p H (which appears to depend on sodium-proton exchange) and ADP (which may be fixed largely by mitochondrial mechanisms) :
we do not yet understand the interplay between these in the control of resting [PCr] and [ADP]. There was no increase in Pi/ATP which is probably (McCully et al. 1988) although not exclusively (Newham & Cady 1990) a feature of muscle damage by eccentric exercise (ie. lengthening contraction), which would have been largely absent in the bicycle exercise reported here. During test exercise PCr/(PCr Pi) was lower after the bicycle ride and the recoveries of PCr and Pi were delayed, with decreased overshoot of PCr/(PCr +Pi). These abnormalities resemble those seen in mitochondrial defects (Arnold et al. 1985), although we could detect no difference in ADP recovery, probably because time resolution was insufficient. However, a mitochondrial defect would also be expected to increase resting [ADP] (Arnold et al. 1985), yet this was not seen. Overshoot of PCr/(PCr Pi) occurs because Pi recovers back to below the resting value. This is thought to result from loss of cytosolic Pi into
+
+
11
G.3. Kemp
et al.
s., KOZAK-REISS, an MRS-invisible mitochondrial Pi pool (Taylor BES'DHAN, D., CONFORT-GOUNY, P.J. 1990. Pi trapping in glycoG. & COZZONE, et a/. 1983) and/or phosphorylated gll-colJ-tic genolytic pathway can explain transient Pi disintermediates (Bendahan et a/.1990). If the first appearance during recovery from muscular exercise. is the dominant process, then the reduced overF E B S Lett 269, 402405. recovery post-ride ma!- also reflect a mild DUAN,J. & KARMAZYN, M. 1990. Reduction of mitochondrial dysfunction. phosphate-induced dysfunction in rat heart mitoT h u s ["PIMRS can detect perturbations of chondria by carnitine. Eur 3 Pharm 189, 163-174. muscle bioenergetics u p to 2 days after strenuous HANDS, L.J., BORE,P.J., GALLOWAY, G., MORRIS, P.J. exercise, broadly consistent with a mild im& RADDA,G.K. 1986. Muscle metabolism in pairment of mitochondrial function. Although patients with peripheral vascular disease investigated by 31P nuclear magnetic resonance specthere may have been some muscle oedema, there troscopy. Clin Sci 71, 283-290. was no convincing enzymological el-idence of D.J., RAJAGOPALAN, B. & RADDA, muscle cell damage and no elevation of Pi/ATP, KEMP,G.J., TAYLOR, G.K. 1991. Bioenergetics of healthy skeletal muscle a previously-reported marker of post-exercise 1-2 days after strenuous exercise. Clin Sri 81, 14P. muscle damage Z., BODEN, B.P., BROWN, R.L., MCCULLY, K., ARGOV, 'The basis of these changes is uncertain. One BASK, W.J. & CHANCE,B. 1986. Detection of possibility is that mitochondria may be damaged muscle injury in humans with 31-P magnetic by their exposure to cytosolic [Pi] of up to resonance spectroscopy. Muscle Nerve 11, 212-216. 20 mol 1- for several hours during the bicycle MCCULLY, M., FOUNK.K., BODEN,B.P., TUCHLER, ride, as similar [Pi] is reported to damage rat TAIN, hl.R. & CHANCE, B. 1989. Wrist flexor muscle of elite rowers measured with magnetic resonance heart mitochondria in ritro (Duan & Karmazyri spectroscopy. f Appl Physiol67, 926-932. 19901. NEWHAM, D.J. & CADY,E.B. 1990. A '*P study of fatigue and metabolism in human skeletal muscle G.J. K \+as supported b! the JIuscular Dystroph) with voluntary, intermittent contractions at differGroup of Great Britain and Northern Ireland. ent forces. N M R in Biomed. 3, 211-219. RADDA, G.K., RAJAGOPALAN, B. & TAYLOR, D.J. 1989. Biochemistry in vivo: an appraisal of clinical REFERENCES magnetic resonance spectroscopy. Mag Res Quart 5, 122-151. ARNOLD, D.L., TAILOR,D.J. & RADD.4, G.K. 1985. D.J., BORE,P.J., STYLES, P., GADIAN, D.G. Investigation of human mitochondrial myopathies TAYLOR, & RADDA, G.K. 1983. Bioenergetics of intact human by phosphorus magnetic resonance spectroscop! . muscle. A 31PNMR study. Mol Biol Med 1, 77-94. Ann .Veurol 18. 189-196.
Bio-energetic changes in human gastrocnemius muscle 1-2 days after strenuous exercise G. J. K E M P , D . J. T A Y L O R , G. K. R A D D A and B. R A J A G O P A L A N MRC Clinical and Biochemical Magnetic Resonance Unit, John Radcliffe Hospital, Oxford, UK KEMP, G. J., TAYLOR, D. J., RADDA,G. K. & RAJAGOPALAN, B. 1992. Bio-energetic changes in human gastrocnemius muscle 1-2 days after strenuous exercise. Actu Phj/siul Scand 146, 11-14. Received 14 January 1992, accepted 4 April 1992. ISSN 00016772. MRC Clinical and Biochemical Magnetic Resonance Unit, John Radcliffe Hospital, Oxford, UK. [31P]magnetic resonance spectroscopy was used to study the metabolic sequelae of intense muscular activity in gastrocnemius of seven subjects 1-2 days after a 67-mile bicycle ride. The muscle was examined at rest, during a test exercise and during recovery from test exercise. Post-ride and pre-ride results were compared. At rest, the ratio of phosphocreatine to ATP (PCr/ATP) was increased post-ride; during test exercise PCr/(PCr+Pi) was lower post-ride; and the recoveries of PCr, Pi and PCr/(PCr Pi) after test exercise were delayed, with decreased ‘overshoot’ of PCr/(PCr+Pi) (which is due to recovery of Pi to below its resting value). Mild mitochondria1 damage (perhaps due to exposure to high cytosolic [Pi] during the bicycle ride) may explain some of these results. In contrast to reports of largely eccentric exercise there was no increase in resting Pi/ATP. We have thus demonstrated perturbations of muscle bio-energetics 1-2 days after strenuous exercise, in the absence of convincing enzymological evidence of muscle damage.
+
Key words: magnetic resonance spectroscopy, exercise, muscle, mitochondria, fatigue, recovery from exercise.
Phosphorus magnetic resonance spectroscopy ([31P]MRS) has been used to detect pathological abnormalities of mitochondrial or glycolytic function in skeletal muscle (Radda et al. 1989) and to demonstrate bio-energetic changes after physical training (McCully et al. 1989) and in fatigue (Newham & Cady 1990). Previous MRS studies have shown high intramuscular phosphate (Pi) concentration persisting for at least 2 days after eccentric and perhaps other exercise (McCully et al. 1988, Newham & Cady 1990). We have used [31P]MRS to investigate the effects of a single bout of prolonged intense muscular activity (a 67-mile bicycle ride) on the bioenergetics of untrained gastrocnemius muscle. Correspondence: Dr G. J. Kernp, MRC Clinical and Biochemical Magnetic Resonance Unit, John Radcliffe Hospital, Headington, Oxford OX3 9DU, UK.
At 1-2 days we found changes in the muscle at rest and in response to test exercise which suggest that MRS can detect minor muscle damage in the absence of appreciable change in plasma ‘muscle’ enzymes. A preliminary account of this work has been presented (Kemp et al. 1991). MATERIALS AND METHODS Seven healthy untrained adults (22-34 years; one male and six female) who undertook a 67-mile bicycle ride for charity were studied by MRS the day before, and either 1 day (four subjects) or 2 days (four subjects), after the ride (for logistic reasons all postride studies could not be carried out on the same day, but no differences were observed between subjects studied 1 and 2 days after the ride). [31P]MR spectra of the right gastrocnemius muscle were obtained from the supine subject as described previously (Hands et al. 1986), using a 6 cm two-turn
11
12
G.3. Kemp
et al.
Table 1. Results of gastrocnemius exercise before and after bicycle ride (mean fSD) Measurement Rest
Mean difference over whole of exercise End of exercise Recovery halftime (s)
Pre-ride Cytosolic pH PCr/ATP Pi/i\TP [ADP] (pmol I-’) PCr/(PCr Pi) PH [ADP] @mol I-’) PCr/(PCr Pi) PH [ADP] (jimol 1 I ) of PCr of Pi of PCr/(PCr Pi) of .4DP at 0.9 min over 2-10 min
+
+
+
Per cent recovery of PCr/(PCr + Pi) Plasmd e n q mes Creatine kinase ’4spartate amino transferase
7.02 f 0.02 2.4 fO.l 0.32 k 0.05 23+4
0.46 k 0.13 6.83i0.19 72f31 2 0 i 11 20f5 19k8 8i3 107 F 14 117k6 Reference range 21--195 15-42
Post-ride 7.02 & 0.02 2.6 0.2 0.31 k 0.08 17k4 - 0.06 i0.03 - 0.03 0.04 4f20 0.40 & 0.12 6.77k0.13 85 2 23 23+8 24+5 24+7 10k4 93+ll 107 2 Post-ride 240+ 133 35 f 15
+
P ns. 0.0003 ns. ns. 0.01 n.s.
ns. n.s. ns. n.s. 0.03 0.02 0.01 n.s. 0.01 0.002 results (range 96-111) (range 13-55)
‘Pre-ride’ and ‘post-ride’ refer to data obtained before and 1-2 days after the bicycle ride. ‘Mean difference over whole exercise’ is the overall mean of the average differences between values at matched time points during test exercise (i.e. post- minus pre-ride, averaged over the whole of exercise for each subject). Plasma enzymes were only obtained post-ride and are compared with the laboratory reference range. Data are compared by paired t-test
surface coil in a 1.9 Tesla superconducting magnet (Oxford Magnet Technologj-, Oxford, UK) interfaced to a Bruker spectrometer (Bruker, Coventry, UK). Pulse-length was 80 p s and interpulse delay 2 s (90’ pulse at coil-centre was 140 ps). Peak areas of Pi, PCi and P-ATP were measured by manual triangulation, pH was calculated from the chemical shift of Pi (Arnold et al. 1985) and since the reaction catalysed by creatine kinase is at equilibrium, free (ADP) was calculated from PCr/ATP and pH (Arnold et al. 1985). The subjects exercised by depressing a pedal at a rate of 30 min-’. The initial load was set at 100,b of lean body mass (Hands et al. 1986) for 5 min, increasing incrementally by 6 o,, of lean body mass each 1.25 min for a total of up to 15 min. Spectra were obtained during 10 min of recovery and recovery halftimes were estimated by interpolation using plots of fractional recover). against time. Creatine kinase and aspartate aminotransferase were measured on plasma samples obtained at the time of the post-ride study by standard methods on a Technicon RAlOOO analyser (Technicon, Basingstoke, UK) . Data are presented as mean SD, and differences are analysed by paired t-test.
+
RESULTS In resting muscle, compared to pre-ride data (Table l), PCr/ATP was increased by 10% post-ride. There were no other significant differences. Figure 1a, b & c shows the pre- and (2 days) post-ride responses to the test exercise in one subject: results from all were similar but in overall mean data (not shown) between-subject variation obscures the pre-post difference. Calculated over the whole of exercise for each subject, mean p H and PCr/(PCr Pi) were lower post-ride (Table l), while the ADP response did not differ significantly. Figure I d shows the recovery of PCr/ (PCr + Pi) after test exercise in a single subject. In all subjects the recovery half-times of [Pi], [PCr] and PCr/(PCr + Pi) were increased postride compared to pre-ride (Table 1). Pre-ride, PCr/(PCr+ Pi) recovered to 100% at 0.75 min and reached a stable value of 120% from 2-10 min; post-ride, it reached lOOyo only at
+
Muscle changes after strenuous exercise 7.101
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;
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Minutes of exercise
Minutes of exercise
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d
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125 100 75
*
50
a
25
z 0
1
2
4
6 8 Minute of exercise
10
2
12
4
;
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lb
Minutes of recovery
Figure 1. [31P]MRSdata from gastrocnemius muscle in one representativefemale subject during test exercise (0, pre-ride; 0 , 2 days post-ride) showing response of ( a ) PCr/(PCr Pi), which is an index of phosphocreatine concentration,(b) cytosolic pH and (c) calculated [ADP] during test exercise and ( d ) percentage recovery of PCr/(PCr Pi) after test exercise.
+
+
1.4 min and achieved a stable value of only 108%. The 'overshoot' to more than lOOyo is real: mean recovery from 2-10 min was greater than lOOyo (at least P < 0.05) in all but one subject, pre- and post-ride; the overall means from 2 to 10 min were greater than 100yo,preand post-ride; and this value was greater prethan post-ride (Table 1). Post-ride creatine kinase was above the reference range in three subjects, aspartate aminotransferase in three subjects and both enzymes in only two subjects (Table 1). DISCUSSION Resting PCr/ATP was slightly raised in gastrocnemius 1-2 days after a 67-mile bicycle ride. PCr is in equilibrium (Arnold et al. 1985) with creatine (which is influenced by creatine uptake), cytosolic p H (which appears to depend on sodium-proton exchange) and ADP (which may be fixed largely by mitochondrial mechanisms) :
we do not yet understand the interplay between these in the control of resting [PCr] and [ADP]. There was no increase in Pi/ATP which is probably (McCully et al. 1988) although not exclusively (Newham & Cady 1990) a feature of muscle damage by eccentric exercise (ie. lengthening contraction), which would have been largely absent in the bicycle exercise reported here. During test exercise PCr/(PCr Pi) was lower after the bicycle ride and the recoveries of PCr and Pi were delayed, with decreased overshoot of PCr/(PCr +Pi). These abnormalities resemble those seen in mitochondrial defects (Arnold et al. 1985), although we could detect no difference in ADP recovery, probably because time resolution was insufficient. However, a mitochondrial defect would also be expected to increase resting [ADP] (Arnold et al. 1985), yet this was not seen. Overshoot of PCr/(PCr Pi) occurs because Pi recovers back to below the resting value. This is thought to result from loss of cytosolic Pi into
+
+
11
G.3. Kemp
et al.
s., KOZAK-REISS, an MRS-invisible mitochondrial Pi pool (Taylor BES'DHAN, D., CONFORT-GOUNY, P.J. 1990. Pi trapping in glycoG. & COZZONE, et a/. 1983) and/or phosphorylated gll-colJ-tic genolytic pathway can explain transient Pi disintermediates (Bendahan et a/.1990). If the first appearance during recovery from muscular exercise. is the dominant process, then the reduced overF E B S Lett 269, 402405. recovery post-ride ma!- also reflect a mild DUAN,J. & KARMAZYN, M. 1990. Reduction of mitochondrial dysfunction. phosphate-induced dysfunction in rat heart mitoT h u s ["PIMRS can detect perturbations of chondria by carnitine. Eur 3 Pharm 189, 163-174. muscle bioenergetics u p to 2 days after strenuous HANDS, L.J., BORE,P.J., GALLOWAY, G., MORRIS, P.J. exercise, broadly consistent with a mild im& RADDA,G.K. 1986. Muscle metabolism in pairment of mitochondrial function. Although patients with peripheral vascular disease investigated by 31P nuclear magnetic resonance specthere may have been some muscle oedema, there troscopy. Clin Sci 71, 283-290. was no convincing enzymological el-idence of D.J., RAJAGOPALAN, B. & RADDA, muscle cell damage and no elevation of Pi/ATP, KEMP,G.J., TAYLOR, G.K. 1991. Bioenergetics of healthy skeletal muscle a previously-reported marker of post-exercise 1-2 days after strenuous exercise. Clin Sri 81, 14P. muscle damage Z., BODEN, B.P., BROWN, R.L., MCCULLY, K., ARGOV, 'The basis of these changes is uncertain. One BASK, W.J. & CHANCE,B. 1986. Detection of possibility is that mitochondria may be damaged muscle injury in humans with 31-P magnetic by their exposure to cytosolic [Pi] of up to resonance spectroscopy. Muscle Nerve 11, 212-216. 20 mol 1- for several hours during the bicycle MCCULLY, M., FOUNK.K., BODEN,B.P., TUCHLER, ride, as similar [Pi] is reported to damage rat TAIN, hl.R. & CHANCE, B. 1989. Wrist flexor muscle of elite rowers measured with magnetic resonance heart mitochondria in ritro (Duan & Karmazyri spectroscopy. f Appl Physiol67, 926-932. 19901. NEWHAM, D.J. & CADY,E.B. 1990. A '*P study of fatigue and metabolism in human skeletal muscle G.J. K \+as supported b! the JIuscular Dystroph) with voluntary, intermittent contractions at differGroup of Great Britain and Northern Ireland. ent forces. N M R in Biomed. 3, 211-219. RADDA, G.K., RAJAGOPALAN, B. & TAYLOR, D.J. 1989. Biochemistry in vivo: an appraisal of clinical REFERENCES magnetic resonance spectroscopy. Mag Res Quart 5, 122-151. ARNOLD, D.L., TAILOR,D.J. & RADD.4, G.K. 1985. D.J., BORE,P.J., STYLES, P., GADIAN, D.G. Investigation of human mitochondrial myopathies TAYLOR, & RADDA, G.K. 1983. Bioenergetics of intact human by phosphorus magnetic resonance spectroscop! . muscle. A 31PNMR study. Mol Biol Med 1, 77-94. Ann .Veurol 18. 189-196.
