Corey R. Hart

In vivo evidence of an age-related increase in ATP cost of contraction in the plantar flexor muscles

Impaired skeletal muscle efficiency potentially contributes to the age-related decline in exercise capacity and may explain the altered haemodynamic response to exercise in the elderly. Thus we examined whether (i) the ATP cost of contraction increases with age, and (ii) this results in altered convective O(2) delivery to maintain microvascular oxygenation in the calf muscle. To this aim, we used an integrative experimental approach combining (31)P-MRS (magnetic resonance spectroscopy), Doppler ultrasound imaging and NIRS (near-IR spectroscopy) during dynamic plantar flexion exercise at 40% of WR(max) (maximal power output) in 20 healthy young and 20 older subjects matched for physical activity. The ATP cost of contraction was significantly higher in the old (7.2±4.1 mM/min per W) compared with the young (2.4±1.9 mM/min per W; P<0.05) and this was only significantly correlated with the plantar flexion WR(max) value in the old subjects (r=-0.52; P<0.05). Even when differences in power output were taken into account, end-exercise blood flow (old, 259±168 ml/min per W and young, 134±40 ml/min per W; P<0.05) and convective O(2) delivery (old, 0.048±0.031 l/min per W and young, 0.026±0.008 l/min per W; P<0.05) were greater in the old in comparison with the young subjects. In contrast, the NIRS oxyhaemoglobin, deoxyhaemoglobin and microvascular oxygenation indices were not significantly different between the groups (P>0.05). Therefore the present study reveals that, although the peripheral haemodynamic responses to plantar flexion exercise appear to be appropriate, the elevated energy cost of contraction and associated reduction in the WR(max) value in this muscle group may play a role in limiting exercise capacity with age.

Symmorphosis and skeletal muscle V̇O2 max : in vivo and in vitro measures reveal differing constraints in the exercise-trained and untrained human.

The concept of symmorphosis predicts that the capacity of each step of the oxygen cascade is attuned to the task demanded of it during aerobic exercise at maximal rates of oxygen consumption ( V̇O2 max ) such that no single process is limiting or in excess at V̇O2 max . The present study challenges the applicability of this concept to humans by revealing clear, albeit very different, limitations and excesses in oxygen supply and consumption among untrained and endurance‐trained humans. Among untrained individuals, V̇O2 max is limited by the capacity of the mitochondria to consume oxygen, despite an excess of oxygen supply, whereas, among trained individuals, V̇O2 max is limited by the supply of oxygen to the mitochondria, despite an excess of mitochondrial respiratory capacity.

Short-term training alters the control of mitochondrial respiration rate before maximal oxidative ATP synthesis

Short‐term exercise training may induce metabolic and performance adaptations before any changes in mitochondrial enzyme potential. However, there has not been a study that has directly assessed changes in mitochondrial oxidative capacity or metabolic control as a consequence of such training in vivo. Therefore, we used 31P‐magnetic resonance spectroscopy (31P‐MRS) to examine the effect of short‐term plantar flexion exercise training on phosphocreatine (PCr) recovery kinetics and the control of respiration rate.

The impact of ageing on adipose structure, function and vasculature in the B6D2F1 mouse: evidence of significant multisystem dysfunction

Dysfunction in the adipose tissue, characterized by reduced adipocyte size, tissue fibrosis and ectopic lipid accumulation, has been implicated in age‐associated metabolic dysfunction, but it is not known how ageing affects the function of the arteries and mitochondria within the adipose tissue. Mitochondrial lipid utilization is impaired in adipose tissue of old mice, evidenced by reduced substrate control ratios in the presence of lipid substrates and is concomitant with increased oxidative stress. Ageing leads to endothelial dysfunction, evidenced by reduced endothelium‐dependent dilation in resistance arteries, reduced angiogenic capacity and reduced vascularity of the adipose tissue. These results indicate that arterial and mitochondrial dysfunction accompany age‐associated adipose tissue and systemic metabolic dysfunction and suggest that targeting arterial or mitochondrial function to improve adipose tissue function may have important application in the treatment of age‐associated metabolic dysfunction.

Mitochondrial function and increased convective O2 transport: implications for the assessment of mitochondrial respiration in vivo

Although phosphorus magnetic resonance spectroscopy (31P-MRS)-based evidence suggests that in vivo peak mitochondrial respiration rate in young untrained adults is limited by the intrinsic mitochondrial capacity of ATP synthesis, it remains unknown whether a large, locally targeted increase in convective O2 delivery would alter this interpretation. Consequently, we examined the effect of superimposing reactive hyperemia (RH), induced by a period of brief ischemia during the last minute of exercise, on oxygen delivery and mitochondrial function in the calf muscle of nine young adults compared with free-flow conditions (FF). To this aim, we used an integrative experimental approach combining 31P-MRS, Doppler ultrasound imaging, and near-infrared spectroscopy. Limb blood flow [area under the curve (AUC), 1.4 ± 0.8 liters in FF and 2.5 ± 0.3 liters in RH, P < 0.01] and convective O2 delivery (AUC, 0.30 ± 0.16 liters in FF and 0.54 ± 0.05 liters in RH, P < 0.01), were significantly increased in RH compared with FF. RH was also associated with significantly higher capillary blood flow (P < 0.05) and faster tissue reoxygenation mean response times (70 ± 15 s in FF and 24 ± 15 s in RH, P < 0.05). This resulted in a 43% increase in estimated peak mitochondrial ATP synthesis rate (29 ± 13 mM/min in FF and 41 ± 14 mM/min in RH, P < 0.05) whereas the phosphocreatine (PCr) recovery time constant in RH was not significantly different (P = 0.22). This comprehensive assessment of local skeletal muscle O2 availability and utilization in untrained subjects reveals that mitochondrial function, assessed in vivo by 31P-MRS, is limited by convective O2 delivery rather than an intrinsic mitochondrial limitation.

Evidence of Preserved Oxidative Capacity and Oxygen Delivery in the Plantar Flexor Muscles With Age.

Studies examining the effect of aging on skeletal muscle oxidative capacity have yielded equivocal results; however, these investigations may have been confounded by differences in oxygen (O(2)) delivery, physical activity, and small numbers of participants. Therefore, we evaluated skeletal muscle oxidative capacity and O(2) delivery in a relatively large group (N = 40) of young (22 ± 2 years) and old (73 ± 7 years) participants matched for physical activity. After submaximal dynamic plantar flexion exercise, phosphocreatine (PCr) resynthesis ((31)P magnetic resonance spectroscopy), muscle reoxygenation (near-infrared spectroscopy), and popliteal artery blood flow (Doppler ultrasound) were measured. The phosphocreatine recovery time constant (Tau) (young: 33 ± 16; old: 30 ± 11 seconds), maximal rate of adenosine triphosphate (ATP) synthesis (young: 25 ± 9; old: 27 ± 8 mM/min), and muscle reoxygenation rates determined by the deoxyhemoglobin/myoglobin recovery Tau (young: 48 ± 5; old: 47 ± 9 seconds) were similar between groups. Similarly, although tending to be higher in the old, there were no significant age-related differences in postexercise popliteal blood flow (area under the curve: young: 1,665 ± 227 vs old: 2,404 ± 357 mL, p = .06) and convective O(2) delivery (young: 293 ± 146 vs old: 404 ± 191 mL, p = .07). In conclusion, when physical activity and O(2) delivery are similar, oxidative capacity in the plantar flexors is not affected by aging. These findings reveal that diminished skeletal muscle oxidative capacity is not an obligatory accompaniment to the aging process.

Impact of age on exercise-induced ATP supply during supramaximal plantar flexion in humans

Currently, the physiological factors responsible for exercise intolerance and bioenergetic alterations with age are poorly understood due, at least in art, to the confounding effect of reduced physical activity in the elderly. Thus, in 40 healthy young (22 ± 2 yr) and old (74 ± 8 yr) activity-matched subjects, we assessed the impact of age on: 1) the relative contribution of the three major pathways of ATP synthesis (oxidative ATP synthesis, glycolysis, and the creatine kinase reaction) and 2) the ATP cost of contraction during high-intensity exercise. Specifically, during supramaximal plantar flexion (120% of maximal aerobic power), to stress the functional limits of the skeletal muscle energy systems, we used (31)P-labeled magnetic resonance spectroscopy to assess metabolism. Although glycolytic activation was delayed in the old, ATP synthesis from the main energy pathways was not significantly different between groups. Similarly, the inferred peak rate of mitochondrial ATP synthesis was not significantly different between the young (25 ± 8 mM/min) and old (24 ± 6 mM/min). In contrast, the ATP cost of contraction was significantly elevated in the old compared with the young (5.1 ± 2.0 and 3.7 ± 1.7 mM·min(-1)·W(-1), respectively; P < 0.05). Overall, these findings suggest that, when young and old subjects are activity matched, there is no evidence of age-related mitochondrial and glycolytic dysfunction. However, this study does confirm an abnormal elevation in exercise-induced skeletal muscle metabolic demand in the old that may contribute to the decline in exercise capacity with advancing age.

Sex-specific impact of aging on the blood pressure response to exercise

An exaggerated blood pressure (BP) response to exercise has been linked to cardiovascular disease, but little is known about the impact of age and sex on this response. Therefore, this study examined the hemodynamic and skeletal muscle metabolic response to dynamic plantar flexion exercise, at 40% of maximum plantar flexion work rate, in 40 physical activity-matched young (23 ± 1 yr, n = 20) and old (73 ± 2 yr, n = 20), equally distributed, male and female subjects. Central hemodynamics and BP (finometer), popliteal artery blood flow (Doppler ultrasound), and skeletal muscle metabolism (31P-magnetic resonance spectroscopy) were measured during 5 min of plantar flexion exercise. Popliteal artery blood flow and high-energy phosphate responses to exercise were not affected by age or sex, whereas aging, independent of sex, attenuated stroke volume and cardiac output responses. Systolic BP and mean arterial pressure responses were exaggerated in old women (Δ42 ± 4 and Δ28 ± 3 mmHg, respectively), with all other groups exhibiting similar increases in systolic BP (old men: Δ27 ± 8 mmHg, young men: Δ27 ± 3 mmHg, and young women: Δ22 ± 3 mmHg) and mean arterial pressure (old men: Δ15 ± 4 mmHg, young men: Δ19 ± 2 mmHg, and young women: Δ17 ± 2 mmHg). Interestingly, the exercise-induced change in systemic vascular resistance in old women (∆0.8 ± 1.0 mmHg·l-1·min-1) was augmented compared with young women and young and old men (∆-2.8 ± 0.5, ∆-1.6 ± 0.6, and ∆-3.18 ± 1.4 mmHg·l-1·min-1, respectively, P < 0.05). Thus, in combination, advancing age and female sex results in an exaggerated BP response to exercise, likely the result of a failure to reduce systemic vascular resistance. NEW & NOTEWORTHY An exaggerated blood pressure response to exercise has been linked to cardiovascular disease; however, little is known about how age and sex impact this response in healthy individuals. During dynamic exercise, older women exhibited an exaggerated blood pressure response driven by an inability to lower systemic vascular resistance.

SINGLE PASSIVE LEG MOVEMENT INDUCED-HYPEREMIA: A SIMPLE VASCULAR FUNCTION ASSESSMENT WITHOUT A CHRONOTROPIC RESPONSE

Passive leg movement (PLM)-induced hyperemia is a novel approach to assess vascular function, with a potential clinical role. However, in some instances, the varying chronotropic response induced by PLM has been proposed to be a potentially confounding factor. Therefore, we simplified and modified the PLM model to require just a single PLM (sPLM), an approach that may evoke a peripheral hemodynamic response, allowing a vascular function assessment, but at the same time minimizing central responses. To both characterize and assess the utility of sPLM, in 12 healthy subjects, we measured heart rate (HR), stroke volume, cardiac output (CO), mean arterial pressure (MAP), leg blood flow (LBF), and calculated leg vascular conductance (LVC) during both standard PLM, consisting of passive knee flexion and extension performed at 1 Hz for 60 s, and sPLM, consisting of only a single passive knee flexion and extension over 1 s. During PLM, MAP transiently decreased (5 ± 1 mmHg), whereas both HR and CO increased from baseline (6.0 ± 1.1 beats/min, and 0.8 ± 0.01 l/min, respectively). Following sPLM, MAP fell similarly (5 ± 2 mmHg; P = 0.8), but neither HR nor CO responses were identifiable. The peak LBF and LVC response was similar for PLM (993 ± 189 ml/min; 11.9 ± 1.5 ml·min-1·mmHg-1, respectively) and sPLM (878 ± 119 ml/min; 10.9 ± 1.6 ml·min-1·mmHg-1, respectively). Thus sPLM represents a variant of the PLM approach to assess vascular function that is more easily performed and evokes a peripheral stimulus that induces a significant hyperemia, but does not generate a potentially confounding, chronotropic response, which may make sPLM more useful clinically. NEW & NOTEWORTHY Using the single passive leg movement (PLM) technique, a variant of the vascular function assessment PLM, we have identified a novel peripheral vascular assessment method that is more easily performed than PLM, which, by not evoking potentially confounding central hemodynamic responses, may be more useful clinically.

Comments on point:counterpoint: skeletal muscle mechanical efficiency does/does not increase with age.

TO THE EDITOR: There is little doubt that the cost of locomotion is impaired with age as it is evident that centenarians, due to their exceptional longevity, present unique adaptations in their skeletal muscle efficiency to compensate for their extremely low VO2max. However, the underlying question of whether skeletal muscle efficiency is altered with age is unsettled (4, 6). In fact, both opponents present compelling evidence in support of their opinion, and the reason for this disagreement is likely that both authors are looking at different muscles. Indeed, there is accumulating evidence that age-related alterations in skeletal muscle efficiency vary among muscle group. For instance, a selective atrophy, independent of the fiber type, has been documented in skeletal muscles with age (5). It is therefore likely that a similar phenomenon occurs for muscle energetics properties. The suggestion that ATP cost of contraction is improved with age (6) is based on examinations of the tibialis anterior. Interestingly, this muscle also exhibits preserved features with age in terms of mitochondrial efficiency (1) and oxidative capacity (3). In contrast, reduced oxidative capacity (3), in conjunction with impaired mitochondrial and contractile efficiency (2), has been documented in the quadriceps, which would, at least partially, explain the increased cost of locomotion with age as this muscle group is a major contributor to force production during these activities. The reasons for the heterogeneous effect of aging on skeletal muscle efficiency remain unclear, but likely stem from differences in fiber type and chronic load associated with locomotion.