Pioglitazone-induced improvements in insulin sensitivity occur without concomitant changes in muscle mitochondrial function.

AIMS: Pioglitazone (Pio) is known to improve insulin sensitivity in skeletal muscle. However, the role of Pio in skeletal muscle lipid metabolism and skeletal muscle oxidative capacity is not clear. The aim of this study was to determine the effects of chronic Pio treatment on skeletal muscle mitochondrial activity in individuals with type 2 diabetes (T2D). MATERIALS AND METHODS: Twenty-four participants with T2D (13M/11F 53.38±2.1years; BMI 36.47±1.1kg/m2) were randomized to either a placebo (CON, n=8) or a pioglitazone (PIO, n=16) group. Following 12weeks of treatment, we measured insulin sensitivity by hyperinsulinemic-euglycemic clamp (clamp), metabolic flexibility by calculating the change in respiratory quotient (ΔRQ) during the steady state of the clamp, intra- and extra-myocellular lipid content (IMCL and EMCL, respectively) by 1H magnetic resonance spectroscopy (1H-MRS) and muscle maximal ATP synthetic capacity (ATPmax) by 31P-MRS. RESULTS: Following 12weeks of PIO treatment, insulin sensitivity (p<0.0005 vs. baseline) and metabolic flexibility (p<0.05 vs. CON) significantly increased. PIO treatment significantly decreased IMCL content and increased EMCL content in gastrocnemius, soleus and tibialis anterior muscles. ATPmax was unaffected by PIO treatment. CONCLUSIONS: These results suggest that 12weeks of pioglitazone treatment improves insulin sensitivity, metabolic flexibility and myocellular lipid distribution without any effect on maximal ATP synthetic capacity in skeletal muscle. Consequently, pioglitazone-induced enhancements in insulin responsiveness and fuel utilization are independent of mitochondrial function.

Mitochondrial NAD(P)H In vivo: Identifying Natural Indicators of Oxidative Phosphorylation in the (31)P Magnetic Resonance Spectrum.

Natural indicators provide intrinsic probes of metabolism, biogenesis and oxidative protection. Nicotinamide adenine dinucleotide metabolites (NAD(P)) are one class of indicators that have roles as co-factors in oxidative phosphorylation, glycolysis, and anti-oxidant protection, as well as signaling in the mitochondrial biogenesis pathway. These many roles are made possible by the distinct redox states (NAD(P)(+) and NAD(P)H), which are compartmentalized between cytosol and mitochondria. Here we provide evidence for detection of NAD(P)(+) and NAD(P)H in separate mitochondrial and cytosol pools in vivo in human tissue by phosphorus magnetic resonance spectroscopy ((31)P MRS). These NAD(P) pools are identified by chemical standards (NAD(+), NADP(+), and NADH) and by physiological tests. A unique resonance reflecting mitochondrial NAD(P)H is revealed by the changes elicited by elevation of mitochondrial oxidation. The decline of NAD(P)H with oxidation is matched by a stoichiometric rise in the NAD(P)(+) peak. This unique resonance also provides a measure of the improvement in mitochondrial oxidation that parallels the greater phosphorylation found after exercise training in these elderly subjects. The implication is that the dynamics of the mitochondrial NAD(P)H peak provides an intrinsic probe of the reversal of mitochondrial dysfunction in elderly muscle. Thus, non-invasive detection of NAD(P)(+) and NAD(P)H in cytosol vs. mitochondria yields natural indicators of redox compartmentalization and sensitive intrinsic probes of the improvement of mitochondrial function with an intervention in human tissues in vivo. These natural indicators hold the promise of providing mechanistic insight into metabolism and mitochondrial function in vivo in a range of tissues in health, disease and with treatment.

The relationship between mitochondrial function and walking performance in older adults with a wide range of physical function.

BACKGROUND: Age related declines in walking performance may be partly attributable to skeletal muscle mitochondrial dysfunction as mitochondria produce over 90% of ATP needed for movement and the capacity for oxidative phosphorylation decreases with age. METHODS: Participants were from two studies: an ancillary to the Lifestyle Interventions and Independence for Elders (LIFE) Study (n=33), which recruited lower functioning participants (Short Physical Performance Battery [SPPB], 7.8±1.2), and the Study of Energy and Aging-Pilot (SEA, n=29), which enrolled higher functioning (SPPB, 10.8±1.4). Physical activity was measured objectively using the Actigraph accelerometer (LIFE) and SenseWear Pro armband (SEA). Phosphocreatine recovery following muscle contraction of the quadriceps was measured using (31)P magnetic resonance spectroscopy and ATPmax (mM ATP/s) was calculated. Walking performance was defined as time (s) to walk 400m at a usual-pace. The cross-sectional association between mitochondrial function and walking performance was assessed using multivariable linear regression. RESULTS: Participants were 77.6±5.3years, 64.2% female and 67.2% white. ATPmax was similar in LIFE vs. SEA (0.52±0.14 vs. 0.55±0.14, p=0.31), despite different function and activity levels (1.6±2.2 vs.77.4±73.3min of moderate activity/day, p<0.01). Higher ATPmax was related to faster walk-time in SEA (r(2)=0.19, p=0.02,); but not the LIFE (r(2)<0.01, p=0.74) cohort. CONCLUSIONS: Mitochondrial function was associated with walking performance in higher functioning, active older adults, but not lower functioning, sedentary older adults.

Muscle force, work and cost: a novel technique to revisit the Fenn effect.

Muscle produces force by forming cross-bridges, using energy released from ATP. While the magnitude and duration of force production primarily determine the energy requirement, nearly a century ago Fenn observed that muscle shortening or lengthening influenced energetic cost of contraction. When work is done by the muscle, the energy cost is increased and when work is done on the muscle the energy cost is reduced. However, the magnitude of the 'Fenn effect' and its mirror ('negative Fenn effect') have not been quantitatively resolved. We describe a new technique coupling magnetic resonance spectroscopy with an in vivo force clamp that can directly quantify the Fenn effect [E=I+W, energy liberated (E) equals the energy cost of isometric force production (I) plus the work done (W)] and the negative Fenn effect (E=I-W) for one muscle, the first dorsal interosseous (FDI). ATP cost was measured during a series of contractions, each of which occurred at a constant force and for a constant duration, thus constant force-time integral (FTI). In all subjects, as the FTI increased with load, there was a proportional linear increase in energy cost. In addition, the cost of producing force greatly increased when the muscle shortened, and was slightly reduced during lengthening contraction. These results, though limited to a single muscle, contraction velocity and muscle length change, do quantitatively support the Fenn effect. We speculate that they also suggest that an elastic element within the FDI muscle functions to preserve the force generated within the cross-bridges.

Skeletal Muscle Mitochondrial Function and Fatigability in Older Adults.

BACKGROUND: Fatigability increases while the capacity for mitochondrial energy production tends to decrease significantly with age. Thus, diminished mitochondrial function may contribute to higher levels of fatigability in older adults. METHODS: The relationship between fatigability and skeletal muscle mitochondrial function was examined in 30 participants aged 78.5 ± 5.0 years (47% female, 93% white), with a body mass index of 25.9 ± 2.7 kg/m(2) and usual gait-speed of 1.2 ± 0.2 m/s. Fatigability was defined using rating of perceived exertion (6-20 point Borg scale) after a 5-minute treadmill walk at 0.72 m/s. Phosphocreatine recovery in the quadriceps was measured using (31)P magnetic resonance spectroscopy and images of the quadriceps were captured to calculate quadriceps volume. ATPmax (mM ATP/s) and oxidative capacity of the quadriceps (ATPmax·Quadriceps volume) were calculated. Peak aerobic capacity (VO2peak) was measured using a modified Balke protocol. RESULTS: ATPmax·Quadriceps volume was associated with VO2peak and was 162.61mM ATP·mL/s lower (p = .03) in those with high (rating of perceived exertion ≥10) versus low (rating of perceived exertion ≤9) fatigability. Participants with high fatigability required a significantly higher proportion of VO2peak to walk at 0.72 m/s compared with those with low fatigability (58.7 ± 19.4% vs 44.9 ± 13.2%, p < .05). After adjustment for age and sex, higher ATPmax was associated with lower odds of having high fatigability (odds ratio: 0.34, 95% CI: 0.11-1.01, p = .05). CONCLUSIONS: Lower capacity for oxidative phosphorylation in the quadriceps, perhaps by contributing to lower VO2peak, is associated with higher fatigability in older adults.

Exercise efficiency is reduced by mitochondrial uncoupling in the elderly.

A reduction in exercise efficiency accompanies ageing in humans. Here we evaluated the impact of changes in the contractile-coupling and mitochondrial-coupling efficiencies on the reduction in exercise efficiency in the elderly. Nine adult (mean, 38.8 years old) and 40 elderly subjects (mean, 68.8 years old) performed a cycle ergometer test to measure O2 uptake and leg power output up to the aerobic limit ( ). Reduced leg power output per unit O2 uptake was reflected in a drop in delta efficiency (εD) from 0.27 ± 0.01 (mean ± SEM) in adults to 0.22 ± 0.01 in the elderly group. Similar declines with age were apparent for both the leg power output at and the ATP generation capacity (ATPmax) determined in vivo using (31)P magnetic resonance spectroscopy. These similar declines resulted in unchanged contractile-coupling efficiency values (εC) in the adult (0.50 ± 0.05) versus the elderly group (0.58 ± 0.04) and agreed with independent measures of muscle contractile-coupling efficiency in human quadriceps (0.5). The mitochondrial-coupling efficiency calculated from the ratio of delta to contractile-coupling efficiencies in the adults (εD/εC = 0.58 ± 0.08) corresponded to values for well-coupled mitochondria (0.6); however, εD/εC was significantly lower in the elderly subjects (0.44 ± 0.03). Conversion of ATPmax per mitochondrial volume (ATPmax/Vv[mt,f]) reported in these groups into thermodynamic units confirmed this drop in mitochondrial-coupling efficiency from 0.57 ± 0.08 in adults to 0.41 ± 0.03 in elderly subjects. Thus, two independent methods revealed that reduced mitochondrial-coupling efficiency was a key part of the drop in exercise efficiency in these elderly subjects and may be an important part of the loss of exercise performance with age.

Elevated energy coupling and aerobic capacity improves exercise performance in endurance-trained elderly subjects.

Increased maximal oxygen uptake (V(O(2)max)), mitochondrial capacity and energy coupling efficiency are reported after endurance training (ET) in adult subjects. Here we test whether leg exercise performance (power output of the legs, P(max), at V(O(2)max)) reflects these improvements with ET in the elderly. Fifteen male and female subjects were endurance trained for a 6 month programme, with 13 subjects (69.5 ± 1.2 years old, range 65-80 years old; n = 7 males; n = 6 females) completing the study. This training significantly improved P(max) (Δ17%; P = 0.003), V(O(2)max) (Δ5.4%; P = 0.021) and the increment in oxygen uptake (V(O(2))) above resting (ΔV(O(2)m-r) = V(O(2)max) - V(O(2)rest; Δ9%; P < 0.02). In addition, evidence of improved energy coupling came from elevated leg power output per unit V(O(2))at the aerobic capacity [Δ(P(max)/ΔV(O(2)m-r)); P = 0.02] and during submaximal exercise in the ramp test as measured by delta efficiency (ΔP(ex)/ΔV(O(2)); P = 0.04). No change was found in blood lactate, muscle glycolysis or fibre type. The rise in P(max) paralleled the improvement in muscle oxidative phosphorylation capacity (ATP(max)) in these subjects. In addition, the greater exercise energy coupling [Δ(P(max)/ΔV(O(2)m-r)) and delta efficiency] was accompanied by increased mitochondrial energy coupling as measured by elevated ATP production per unit mitochondrial content in these subjects. These results suggest that leg exercise performance benefits from elevations in energy coupling and oxidative phosphorylation capacity at both the whole-body and muscle levels that accompany endurance training in the elderly.

Skeletal muscle mitochondrial energetics are associated with maximal aerobic capacity and walking speed in older adults.

BACKGROUND: Lower ambulatory performance with aging may be related to a reduced oxidative capacity within skeletal muscle. This study examined the associations between skeletal muscle mitochondrial capacity and efficiency with walking performance in a group of older adults. METHODS: Thirty-seven older adults (mean age 78 years; 21 men and 16 women) completed an aerobic capacity (VO2 peak) test and measurement of preferred walking speed over 400 m. Maximal coupled (State 3; St3) mitochondrial respiration was determined by high-resolution respirometry in saponin-permeabilized myofibers obtained from percutanous biopsies of vastus lateralis (n = 22). Maximal phosphorylation capacity (ATPmax) of vastus lateralis was determined in vivo by (31)P magnetic resonance spectroscopy (n = 30). Quadriceps contractile volume was determined by magnetic resonance imaging. Mitochondrial efficiency (max ATP production/max O2 consumption) was characterized using ATPmax per St3 respiration (ATPmax/St3). RESULTS: In vitro St3 respiration was significantly correlated with in vivo ATPmax (r (2) = .47, p = .004). Total oxidative capacity of the quadriceps (St3*quadriceps contractile volume) was a determinant of VO2 peak (r (2) = .33, p = .006). ATPmax (r (2) = .158, p = .03) and VO2 peak (r (2) = .475, p < .0001) were correlated with preferred walking speed. Inclusion of both ATPmax/St3 and VO2 peak in a multiple linear regression model improved the prediction of preferred walking speed (r (2) = .647, p < .0001), suggesting that mitochondrial efficiency is an important determinant for preferred walking speed. CONCLUSIONS: Lower mitochondrial capacity and efficiency were both associated with slower walking speed within a group of older participants with a wide range of function. In addition to aerobic capacity, lower mitochondrial capacity and efficiency likely play roles in slowing gait speed with age.

Higher mitochondrial respiration and uncoupling with reduced electron transport chain content in vivo in muscle of sedentary versus active subjects.

OBJECTIVE: This study investigated the disparity between muscle metabolic rate and mitochondrial metabolism in human muscle of sedentary vs. active individuals. RESEARCH DESIGN AND METHODS: Chronic activity level was characterized by a physical activity questionnaire and a triaxial accelerometer as well as a maximal oxygen uptake test. The ATP and O(2) fluxes and mitochondrial coupling (ATP/O(2) or P/O) in resting muscle as well as mitochondrial capacity (ATP(max)) were determined in vivo in human vastus lateralis muscle using magnetic resonance and optical spectroscopy on 24 sedentary and seven active subjects. Muscle biopsies were analyzed for electron transport chain content (using complex III as a representative marker) and mitochondrial proteins associated with antioxidant protection. RESULTS: Sedentary muscle had lower electron transport chain complex content (65% of the active group) in proportion to the reduction in ATP(max) (0.69 ± 0.07 vs. 1.07 ± 0.06 mM sec(-1)) as compared with active subjects. This lower ATP(max) paired with an unchanged O(2) flux in resting muscle between groups resulted in a doubling of O(2) flux per ATP(max) (3.3 ± 0.3 vs. 1.7 ± 0.2 µM O(2) per mM ATP) that reflected mitochondrial uncoupling (P/O = 1.41 ± 0.1 vs. 2.1 ± 0.3) and greater UCP3/complex III (6.0 ± 0.7 vs. 3.8 ± 0.3) in sedentary vs. active subjects. CONCLUSION: A smaller mitochondrial pool serving the same O(2) flux resulted in elevated mitochondrial respiration in sedentary muscle. In addition, uncoupling contributed to this higher mitochondrial respiration. This finding resolves the paradox of stable muscle metabolism but greater mitochondrial respiration in muscle of inactive vs. active subjects.

High efficiency in human muscle: an anomaly and an opportunity?

Can human muscle be highly efficient in vivo? Animal muscles typically show contraction-coupling efficiencies <50% in vitro but a recent study reports that the human first dorsal interosseous (FDI) muscle of the hand has an efficiency value in vivo of 68%. We examine two key factors that could account for this apparently high efficiency value: (1) transfer of cross-bridge work into mechanical work and (2) the use of elastic energy to do external work. Our analysis supports a high contractile efficiency reflective of nearly complete transfer of muscular to mechanical work with no contribution by recycling of elastic energy to mechanical work. Our survey of reported contraction-coupling efficiency values puts the FDI value higher than typical values found in small animals in vitro but within the range of values for human muscle in vivo. These high efficiency values support recent studies that suggest lower Ca(2+) cycling costs in working contractions and a decline in cost during repeated contractions. In the end, our analysis indicates that the FDI muscle may be exceptional in having an efficiency value on the higher end of that reported for human muscle. Thus, the FDI muscle may be an exception both in contraction-coupling efficiency and in Ca(2+) cycling costs, which makes it an ideal muscle model system offering prime conditions for studying the energetics of muscle contraction in vivo.

Skeletal muscle NAMPT is induced by exercise in humans.

In mammals, nicotinamide phosphoribosyltransferase (NAMPT) is responsible for the first and rate-limiting step in the conversion of nicotinamide to nicotinamide adenine dinucleotide (NAD+). NAD+ is an obligate cosubstrate for mammalian sirtuin-1 (SIRT1), a deacetylase that activates peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC-1alpha), which in turn can activate mitochondrial biogenesis. Given that mitochondrial biogenesis is activated by exercise, we hypothesized that exercise would increase NAMPT expression, as a potential mechanism leading to increased mitochondrial content in muscle. A cross-sectional analysis of human subjects showed that athletes had about a twofold higher skeletal muscle NAMPT protein expression compared with sedentary obese, nonobese, and type 2 diabetic subjects (P < 0.05). NAMPT protein correlated with mitochondrial content as estimated by complex III protein content (R(2) = 0.28, P < 0.01), MRS-measured maximal ATP synthesis (R(2) = 0.37, P = 0.002), and Vo(2max) (R(2) = 0.63, P < 0.0001). In an exercise intervention study, NAMPT protein increased by 127% in sedentary nonobese subjects after 3 wk of exercise training (P < 0.01). Treatment of primary human myotubes with forskolin, a cAMP signaling pathway activator, resulted in an approximately 2.5-fold increase in NAMPT protein expression, whereas treatment with ionomycin had no effect. Activation of AMPK via AICAR resulted in an approximately 3.4-fold increase in NAMPT mRNA (P < 0.05) as well as modest increases in NAMPT protein (P < 0.05) and mitochondrial content (P < 0.05). These results demonstrate that exercise increases skeletal muscle NAMPT expression and that NAMPT correlates with mitochondrial content. Further studies are necessary to elucidate the pathways regulating NAMPT as well as its downstream effects.

Contraction coupling efficiency of human first dorsal interosseous muscle.

During working contractions, chemical energy in the form of ATP is converted to external work. The efficiency of this conversion, called 'contraction coupling efficiency', is calculated by the ratio of work output to energy input from ATP splitting. Experiments on isolated muscles and permeabilized fibres show the efficiency of this conversion has a wide range, 0.2-0.7. We measured the work output in contractions of a single human hand muscle in vivo and of the ATP cost of that work to calculate the contraction coupling efficiency of the muscle. Five subjects performed six bouts of rapid voluntary contractions every 1.5 s for 42 s (28 contractions, each with time to peak force < 150 ms). The bouts encompassed a 7-fold range of workloads. The ATP cost during work was quantified by measuring the extent of chemical changes within the muscle from (31)P magnetic resonance spectra. Contraction coupling efficiency was determined as the slope of paired measurements of work output and ATP cost at the five graded work loads. The results show that 0.68 of the chemical energy available from ATP splitting was converted to external work output. A plausible mechanism to account for this high value is a substantially lower efficiency for mitochondrial ATP synthesis. The method described here can be used to analyse changes in the overall efficiency determined from oxygen consumption during exercise that can occur in disease or with age, and to test the hypothesis that such changes are due to reduced contraction coupling efficiency.

Mitochondrial dysfunction: impact on exercise performance and cellular aging.

Innovative noninvasive methods open a new window on the cell in vivo. This window reveals that the tempo of mitochondrial dysfunction with age varies among muscles and in proportion to Type II muscle fiber content. Exercise training can reverse age-related dysfunction, thereby providing an intervention to slow the pace of aging and disability in the elderly.

Mild mitochondrial uncoupling impacts cellular aging in human muscles in vivo.

Faster aging is predicted in more active tissues and animals because of greater reactive oxygen species generation. Yet age-related cell loss is greater in less active cell types, such as type II muscle fibers. Mitochondrial uncoupling has been proposed as a mechanism that reduces reactive oxygen species production and could account for this paradox between longevity and activity. We distinguished these hypotheses by using innovative optical and magnetic resonance spectroscopic methods applied to noninvasively measured ATP synthesis and O(2) uptake in vivo in human muscle. Here we show that mitochondrial function is unchanged with age in mildly uncoupled tibialis anterior muscle (75% type I) despite a high respiratory rate in adults. In contrast, substantial uncoupling and loss of cellular [ATP] indicative of mitochondrial dysfunction with age was found in the lower respiring and well coupled first dorsal interosseus (43-50% type II) of the same subjects. These results reject respiration rate as the sole factor impacting the tempo of cellular aging. Instead, they support mild uncoupling as a mechanism protecting mitochondrial function and contributing to the paradoxical longevity of the most active muscle fibers.

Mitochondrial function, fibre types and ageing: new insights from human muscle in vivo.

Mitochondrial changes are at the centre of a wide range of maladies, including diabetes, neurodegeneration and ageing-related dysfunctions. Here we describe innovative optical and magnetic resonance spectroscopic methods that non-invasively measure key mitochondrial fluxes, ATP synthesis and O(2) uptake, to permit the determination of mitochondrial coupling efficiency in vivo (P/O: half the ratio of ATP flux to O(2) uptake). Three new insights result. First, mitochondrial coupling can be measured in vivo with the rigor of a biochemical determination and provides a gold standard to define well-coupled mitochondria (P/O approximately 2.5). Second, mitochondrial coupling differs substantially among muscles in healthy adults, from values reflective of well-coupled oxidative phosphorylation in a hand muscle (P/O = 2.7) to mild uncoupling in a leg muscle (P/O = 2.0). Third, these coupling differences have an important impact on cell ageing. We found substantial uncoupling and loss of cellular [ATP] in a hand muscle indicative of mitochondrial dysfunction with age. In contrast, stable mitochondrial function was found in a leg muscle, which supports the notion that mild uncoupling is protective against mitochondrial damage with age. Thus, greater mitochondrial dysfunction is evident in muscles with higher type II muscle fibre content, which may be at the root of the preferential loss of type II fibres found in the elderly. Our results demonstrate that mitochondrial function and the tempo of ageing varies among human muscles in the same individual. These technical advances, in combination with the range of mitochondrial properties available in human muscles, provide an ideal system for studying mitochondrial function in normal tissue and the link between mitochondrial defects and cell pathology in disease.

Acidosis inhibits oxidative phosphorylation in contracting human skeletal muscle in vivo.

This study tested the hypothesis that acidic pH inhibits oxidative ATP supply during exercise in hand (first dorsal interosseus, FDI) and lower limb (leg anterior compartment, LEG) muscles. We measured oxidative flux and estimated mitochondrial capacity using the changes in creatine phosphate concentration ([PCr]) and pH as detected by 31P magnetic resonance (MR) spectroscopy during isometric exercise and recovery. The highest oxidative ATP flux in sustained exercise was about half the estimated mitochondrial capacity in the LEG (0.38 +/- 0.06 vs. 0.90 +/- 0.14 mM ATP s(-1), respectively), but at the estimated capacity in the FDI (0.61 +/- 0.05 vs. 0.61 +/- 0.09 mM ATP s(-1), respectively). During sustained exercise at a higher contraction rate, intracellular acidosis (pH < 6.88) prevented a rise in oxidative flux in the LEG and FDI despite significantly increased [ADP]. We tested whether oxidative flux could increase above that achieved in sustained exercise by raising [ADP] (> 0.24 mM) and avoiding acidosis using burst exercise. This exercise raised oxidative flux (0.69 +/- 0.05 mM ATP s(-1)) to nearly twice that found with sustained exercise in the LEG and matched (0.65 +/- 0.11 mM ATP s(-1)) the near maximal flux seen during sustained exercise in the FDI. Thus both muscles reached their highest oxidative fluxes in the absence of acidosis. These results show that acidosis inhibits oxidative phosphorylation in vivo and can limit ATP supply in exercising muscle to below the mitochondrial capacity.

Altered energetic properties in skeletal muscle of men with well-controlled insulin-dependent (type 1) diabetes.

This study asked whether the energetic properties of muscles are changed by insulin-dependent diabetes mellitus (or type 1 diabetes), as occurs in obesity and type 2 diabetes. We used (31)P magnetic resonance spectroscopy to measure glycolytic flux, oxidative flux, and contractile cost in the ankle dorsiflexor muscles of 10 men with well-managed type 1 diabetes and 10 age- and activity-matched control subjects. Each subject performed sustained isometric muscle contractions lasting 30 and 120 s while attempting to maintain 70-75% of maximal voluntary contraction force. An altered glycolytic flux in type 1 diabetic subjects relative to control subjects was apparent from significant differences in pH in muscle at rest and at the end of the 120-s bout. Glycolytic flux during exercise began earlier and reached a higher peak rate in diabetic patients than in control subjects. A reduced oxidative capacity in the diabetic patients' muscles was evident from a significantly slower phosphocreatine recovery from a 30-s exercise bout. Our findings represent the first characterization of the energetic properties of muscle from type 1 diabetic patients. The observed changes in glycolytic and oxidative fluxes suggest a diabetes-induced shift in the metabolic profile of muscle, consistent with studies of obesity and type 2 diabetes that point to common muscle adaptations in these diseases.

A "functional biopsy" of muscle properties in sprinters and distance runners.

PURPOSE: Fast- and slow-twitch human muscle fibers exhibit large (two- to threefold) differences in metabolic enzyme activities and contractile economy. We asked whether comparable flux differences are evident in the muscles of athletes specializing in extremely different (i.e., sprint and long-distance) running events. METHODS: We took an in vivo "functional biopsy" of the ankle dorsiflexor muscles of 17 members of a university track team by using (31)P magnetic resonance spectroscopy. Ten sprinters (SPR) and seven distance runners (DIS) performed rapid isometric dorsiflexions against the resistance of a plastic foot holder. The contractile cost of exercise and glycolytic flux were calculated from changes in pH, [PCr], and [P(i)] during ischemic exercise, and oxidative capacity was calculated from PCr recovery kinetics after aerobic exercise. RESULTS: Contractile costs were 47% higher in SPR than in DIS, whereas oxidative capacities were 52% higher in DIS than in SPR. Surprisingly, glycolytic ATP production was similar in the two groups. CONCLUSION: The muscles of SPR and DIS exhibit clear differences in energetic properties, but these differences are smaller than the two- to three-fold variations seen in the properties of individual muscle fibers.