Phosphocreatine Recovery Research Articles

Identifying the Mechanisms of a Peripherally Limited Exercise Phenotype in Patients With Heart Failure With Preserved Ejection Fraction.

We identified peripherally limited patients using cardiopulmonary exercise testing and measured skeletal muscle oxygen transport and utilization during invasive single leg exercise testing to identify the mechanisms of the peripheral limitation. Forty-five patients with heart failure with preserved ejection fraction (70±7 years, 27 females) completed seated upright cardiopulmonary exercise testing and were defined as having a (1) peripheral limitation to exercise if cardiac output/oxygen consumption (VO2) was elevated (≥6) or 5 to 6 with a stroke volume reserve >50% (n=31) or (2) a central limitation to exercise if cardiac output/VO2 slope was ≤5 or 5 to 6 with stroke volume reserve <50% (n=14). Single leg knee extension exercise was used to quantify peak leg blood flow (Doppler ultrasound), arterial-to-venous oxygen content difference (femoral venous catheter), leg VO2, and muscle oxygen diffusive conductance. In a subset of participants (n=36), phosphocreatine recovery time was measured by magnetic resonance spectroscopy to determine skeletal muscle oxidative capacity. Peak VO2 during cardiopulmonary exercise testing was not different between groups (central: 13.9±5.7 versus peripheral: 12.0±3.1 mL/min per kg; P=0.135); however, the peripheral group had a lower peak arterial-to-venous oxygen content difference (central: 13.5±2.0 versus peripheral: 11.1±1.6 mLO2/dL blood; P<0.001). During single leg knee extension, there was no difference in peak leg VO2 (P=0.306), but the peripherally limited group had greater blood flow/VO2 ratio (P=0.024), lower arterial-to-venous oxygen content difference (central: 12.3±2.5 versus peripheral: 10.3±2.2 mLO2/dL blood; P=0.013), and lower muscle oxygen diffusive conductance (P=0.021). A difference in magnetic resonance spectroscopy-derived phosphocreatine recovery time was not detected (P=0.199). Peripherally limited patients with heart failure with preserved ejection fraction identified by cardiopulmonary exercise testing have impairments in oxygen transport and utilization at the level of the skeletal muscle quantified by invasive knee extension exercise testing, which includes an increased blood flow/V̇O2 ratio and poor muscle diffusive capacity. URL: https://www.clinicaltrials.gov; Unique identifier: NCT04068844.

Relationship between skeletal mitochondrial function and digital markers of free-living physical activity in older adults.

This study examined the association between in vivo skeletal mitochondrial function and digital free-living physical activity patterns-a measure that summarizes biological, phenotypic, functional, and environmental effects on mobility. Among 459 participants (mean age 68years; 55% women) in the Baltimore Longitudinal Study of Aging, mitochondrial function was quantified as skeletal muscle oxidative capacity via post-exercise phosphocreatine recovery rate (τPCr) in the vastus lateralis muscle of the left thigh, using 31P magnetic resonance spectroscopy. Accelerometry was collected using a 7-day, 24-h wrist-worn protocol and summarized into activity amount, intensity, endurance, and accumulation patterning metrics. Linear regression, two-part linear and logistic (bout analyses), and linear mixed effects models (time-of-day analyses) were used to estimate associations between τPCr and each physical activity metric. Interactions by age, sex, and gait speed were tested. After covariate adjustment, higher τPCr (or poorer mitochondrial function) was associated with lower activity counts/day (β = - 6593.7, SE = 2406.0; p = 0.006) and activity intensity (- 81.5 counts, SE = 12.9; p < 0.001). For activity intensity, the magnitude of association was greater for men and those with slower gait speed (interaction p < 0.02 for both). Conversely, τPCr was not associated with daily active minutes/day (p = 0.15), activity fragmentation (p = 0.13), or endurance at any bout length (p > 0.05 for all). Time-of-day analyses show participants with high τPCr were less active from 6:00 a.m. to 12:00 a.m. than those with low τPCr. Results indicate that poorer skeletal mitochondrial function is primarily associated with lower engagement in high intensity activities. Our findings help define the connection between laboratory-measured mitochondrial function and real-world physical activity behavior.

A study protocol to investigate if acipimox improves muscle function and sarcopenia: an open-label, uncontrolled, before-and-after experimental medicine feasibility study in community-dwelling older adults

IntroductionSarcopenia is the age-associated loss of muscle mass and strength. Nicotinamide adenine dinucleotide (NAD) plays a central role in both mitochondrial function and cellular ageing processes implicated in sarcopenia. NAD...

Muscle Oxygen Dynamics Measured by NIRS.

Near-infrared spectroscopy (NIRS) has been used to measure skeletal muscle oxidative function for more than 30years. Several indicators evaluate muscle oxidative function using NIRS during exercise, such as deoxygenation rate at the start of exercise (Deoxy-rate), changes in deoxygenation during exercise (ΔDeoxy), and reoxygenation speed after exercise (T1/2 reoxy, reoxy rate). Previous studies have reported that these muscle NIRS indicators are significantly correlated with muscle fibre type, phosphocreatine recovery rate, and peak oxygen uptake. In addition, muscle NIRS indicators have been applied to the study of a number of chronic health conditions, including patients with ischaemic heart failure. Recently, wearable NIRS devices monitor muscle function continuously and freely in the field, and we predict that NIRS devices will be widely applied to our lifestyles more than ever before. However, there are some critical problems with measuring muscle oxidative function using NIRS devices. We have previously reported that subcutaneous adipose tissue thickness (SATT) greatly influences the light pathlength and makes it difficult to quantify tissue deoxygenation, especially in the measurements of muscle deoxygenation from the skin surface. The effects of SATT need to, therefore, be corrected when using NIRS devices, especially when comparing differences in sex, age, and trainability, as the subjects' SATT could differ significantly. In addition, we have more recently reported that assuming constant mean pathlength (MPL) in NIRS leads to an inaccurate interpretation of muscle deoxygenation, since there are greater changes in MPL during incremental cycling exercise, especially at shorter wavelengths in the NIRS region. In this mini-review, we will summarise the indicators of muscle oxidative function using NIRS and the challenges of using an NIRS apparatus, especially during exercise.

Abstract 16878: Exercise Intolerance in Heart Failure With Preserved Ejection Fraction is More Closely Related to Energetic Decline During Exercise Than to Mitochondrial Oxidative Capacity in Recovery

Introduction: Heart failure (HF) with preserved ejection fraction (HFpEF) is associated with severe exercise intolerance (EI) and exertional fatigue. Impaired skeletal muscle high-energy phosphate metabolism has been reported in HFpEF patients and postulated as a potential contributor to EI. However, whether EI is more closely related to rapid energetic decline during exercise, or reduced mitochondrial oxidative capacity remains unknown. Hypothesis: We hypothesized that six-minute walk distance (6MWD) is more closely related to the rate of skeletal muscle energetic decline during exercise than mitochondrial oxidative capacity in HFpEF. Methods: Calf muscle energetics were measured by phosphorus magnetic resonance spectroscopy ( 31 PMRS). The rate of phosphocreatine (PCr) decline normalized to work performed during graded plantar flexion exercise to volitional fatigue and the time for PCr post-exercise recovery, an established metric inversely related to mitochondrial oxidative capacity, were measured in 64 HFpEF patients (age: 65 ± 11 years; 53% women). Results: The mean rate of PCr decline, PCr recovery time, and 6MWD were 52 ± 108 μmol/g wet weight/KJ, 80 ± 45 seconds, and 296 ± 109 meters, respectively. The 6MWD was inversely related to the rate of PCr decline (r = -0.46; P = 0.0002; Figure, A ) but not significantly related to the PCr recovery time (r = -0.06; P = 0.66; Figure, B ), as determined by Pearson’s correlation coefficients. Conclusions: EI, as measured by 6MWD, in HFpEF patients is closely associated with impaired skeletal muscle metabolism, specifically rapid skeletal muscle PCr decline during exercise rather than mitochondrial oxidative capacity. This suggests that impaired glycolytic metabolism and substrate delivery may contribute metabolically to EI in HFpEF patients.

Measurements of in vivo skeletal muscle oxidative capacity are lower following sustained isometric compared with dynamic contractions.

Human skeletal muscle oxidative capacity can be quantified non-invasively using 31-phosphorus magnetic resonance spectroscopy (31P-MRS) to measure the rate constant of phosphocreatine (PCr) recovery (kPCr) following contractions. In the quadricep muscles, several studies have quantified kPCr following 24-30s of sustained maximal voluntary isometric contraction (MVIC). This approach has the advantage of simplicity but is potentially problematic because sustained MVICs inhibit perfusion, which may limit muscle oxygen availability or increase the intracellular metabolic perturbation, and thus affect kPCr. Alternatively, dynamic contractions allow reperfusion between contractions, which may avoid limitations in oxygen delivery. To determine whether dynamic contraction protocols elicit greater kPCr than sustained MVIC protocols, we used a cross-sectional design to compare quadriceps kPCr in 22 young and 11 older healthy adults following 24s of maximal voluntary: (1) sustained MVIC and (2) dynamic (MVDC; 120°·s-1, 1 every 2s) contractions. Muscle kPCr was ∼20% lower following the MVIC protocol compared with the MVDC protocol (p≤0.001), though this was less evident in older adults (p=0.073). Changes in skeletal muscle pH (p≤0.001) and PME accumulation (p≤0.001) were greater following the sustained MVIC protocol, and pH (p≤0.001) and PME (p≤0.001) recovery were slower. These results demonstrate that (i) a brief, sustained MVIC yields a lower value for skeletal muscle oxidative capacity than an MVDC protocol of similar duration and (ii) this difference may not be consistent across populations (e.g., young vs. old). Thus, the potential effect of contraction protocol on comparisons of kPCr in different study groups requires careful consideration in the future.

Evidence for inefficient contraction and abnormal mitochondrial activity in sarcopenia using magnetic resonance spectroscopy.

Mitochondrial dysfunction has been implicated in sarcopenia. 31 P magnetic resonance spectroscopy (MRS) enables non-invasive measurement of adenosine triphosphate (ATP) synthesis rates to probe mitochondrial function. Here, we assessed muscle energetics in older sarcopenic and non-sarcopenic men and compared with muscle biopsy-derived markers of mitochondrial function. Twenty Chinese men with sarcopenia (SARC, age=73.1±4.1years) and 19 healthy aged and sex-matched controls (CON, age=70.3±4.2years) underwent assessment of strength, physical performance, and magnetic resonance imaging. Concentrations of phosphocreatine (PCr), ATP and inorganic phosphate (Pi) as well as muscle pH were measured at rest and during an interleaved rest-exercise protocol to probe muscle mitochondrial function. Results were compared to biopsy-derived mitochondrial complex activity and expression to understand underlying metabolic perturbations. Despite matched muscle contractile power (strength/cross-sectional area), the ATP contractile cost was higher in SARC compared with CON (low-intensity exercise: 1.06±0.59 vs. 0.57±0.22, moderate: 0.93±0.43 vs. 0.58±0.68, high: 0.70±0.57 vs. 0.43±0.51mmolL-1 min-1 bar-1 cm-2 , P=0.003, <0.0001 and <0.0001, respectively). Post-exercise mitochondrial oxidative synthesis rates (a marker of mitochondrial function) tended to be longer in SARC but did not reach significance (17.3±6.4 vs. 14.6±6.5mmolL-1 min-1 , P=0.2). However, relative increases in end-exercise ADP in SARC (31.8±9.9 vs. 24.0±7.3mmolL-1 , P=0.008) may have been a compensatory mechanism. Mitochondrial complex activity was found to be associated with exercise-induced drops in PCr [citrate synthetase activity (CS), Spearman correlation rho=-0.42, P=0.03] and end-exercise ADP (complex III, rho=-0.52, P=0.01; CS rho=-0.45, P=0.02; SDH rho=-0.45, P=0.03), with CS also being strongly associated with the PCr recovery rate following low intensity exercise (rho=-0.47, P=0.02), and the cost of contraction at high intensity (rho=-0.54, P=0.02). Interestingly, at high intensity, the fractional contribution of oxidative phosphorylation to exercise was correlated with activity in complex II (rho=0.5, P=0.03), CS (rho=0.47, P=0.02) and SDH (rho=0.46, P=0.03), linking increased mitochondrial complex activity with increased ability to generate energy through oxidative pathways. This study used 31 P MRS to assess ATP utilization and resynthesis in sarcopenic muscle and demonstrated abnormal increases in the energy cost during exercise and perturbed mitochondrial energetics in recovery. Associations between mitochondrial complex activity and the fractional contribution to energy requirement during exercise indicate increased ability to generate energy oxidatively in those with better mitochondrial complex activity.

Supplementation-induced change in muscle carnosine is paralleled by changes in muscle metabolism, protein glycation and reactive carbonyl species sequestering.

Carnosine is a performance-enhancing food supplement with a potential to modulate muscle energy metabolism and toxic metabolites disposal. In this study we explored interrelations between carnosine supplementation (2 g/day, 12 weeks) induced effects on carnosine muscle loading and parallel changes in (i) muscle energy metabolism, (ii) serum albumin glycation and (iii) reactive carbonyl species sequestering in twelve (M/F=10/2) sedentary, overweight-to-obese (BMI: 30.0+/-2.7 kg/m2) adults (40.1+/-6.2 years). Muscle carnosine concentration (Proton Magnetic Resonance Spectroscopy; 1H-MRS), dynamics of muscle energy metabolism (Phosphorus Magnetic Resonance Spectroscopy; 31P-MRS), body composition (Magnetic Resonance Imaging; MRI), resting energy expenditure (indirect calorimetry), glucose tolerance (oGTT), habitual physical activity (accelerometers), serum carnosine and carnosinase-1 content/activity (ELISA), albumin glycation, urinary carnosine and carnosine-propanal concentration (mass spectrometry) were measured. Supplementation-induced increase in muscle carnosine was paralleled by improved dynamics of muscle post-exercise phosphocreatine recovery, decreased serum albumin glycation and enhanced urinary carnosine-propanal excretion (all p<0.05). Magnitude of supplementation-induced muscle carnosine accumulation was higher in individuals with lower baseline muscle carnosine, who had lower BMI, higher physical activity level, lower resting intramuscular pH, but similar muscle mass and dietary protein preference. Level of supplementation-induced increase in muscle carnosine correlated with reduction of protein glycation, increase in reactive carbonyl species sequestering, and acceleration of muscle post-exercise phosphocreatine recovery.

Muscle Function, Body Composition, Insulin Sensitivity and Physical Activity in Adolescents Born Preterm: Impact of Gestation and Vitamin D Status.

Whilst several studies have explored adolescent metabolic and cognitive function after preterm birth, few have explored muscle function and physical activity. We set out to examine the relationship between gestational age and muscle metabolism in a cohort of adolescents who were born preterm. Participants were recruited from the Newcastle preterm birth growth study cohort. They did not have severe neurological disease and were not on daily medication. Participants underwent an assessment of oxidative muscle function using phosphorus magnetic resonance spectroscopy that included the half-time for recovery of equilibrium of phosphocreatine, τ½PCr. In addition, we measured key variables that might affect muscle function including physical activity levels determined by 3-day accelerometry, body composition using air displacement plethysmography, insulin sensitivity using the homeostatic model assessment/Matsuda index and serum vitamin D concentrations. 60 adolescents (35F) median age 15.6 years (range 12.1−18.8) with a median gestation of 31 weeks (range 24 to 34 weeks) underwent a single assessment. Males were more active and spent less time in sedentary mode. Time spent in light activity was associated with insulin sensitivity (IS) (Matsuda Index; p < 0.05) but there were no strong correlations between activity levels and gestational age. Greater fat mass, waist circumference and body mass index were all associated with lower IS. Gestational age was negatively associated with adjusted measures of oxidative muscle function (τ½PCr). In a stepwise multivariate linear regression model, gestational age at birth was the most significant predictor of oxidative muscle function (p = 0.005). Higher serum vitamin D levels were also associated with faster phosphocreatine recovery time (p = 0.045). Oxidative function in the skeletal muscle of adolescents born preterm is associated with gestational age and vitamin D concentrations. Our study suggests that being born preterm may have a long-term impact on muscle metabolism.

Effects of SGLT2 inhibitor dapagliflozin in patients with type 2 diabetes on skeletal muscle cellular metabolism

ObjectiveSGLT2 inhibitors increase urinary glucose excretion and have beneficial effects on cardiovascular and renal outcomes; the underlying mechanism may be metabolic adaptations due to urinary glucose loss. Here, we investigated the cellular and molecular effects of 5 weeks of dapagliflozin treatment on skeletal muscle metabolism in type 2 diabetes patients. MethodsTwenty-six type 2 diabetes mellitus patients were randomized to a 5-week double-blind, cross-over study with 6-8-week wash-out. Skeletal muscle acetylcarnitine levels, intramyocellular lipid (IMCL) content and phosphocreatine (PCr) recovery rate were measured by magnetic resonance spectroscopy (MRS). Ex vivo mitochondrial respiration was measured in skeletal muscle fibers using high resolution respirometry. Intramyocellular lipid droplet and mitochondrial network dynamics were investigated using confocal microscopy. Skeletal muscle levels of acylcarnitines, amino acids and TCA cycle intermediates were measured. Expression of genes involved in fatty acid metabolism were investigated. ResultsMitochondrial function, mitochondrial network integrity and citrate synthase and carnitine acetyltransferase activities in skeletal muscle were unaltered after dapagliflozin treatment. Dapagliflozin treatment increased intramyocellular lipid content (0.060 (0.011, 0.110) %, p = 0.019). Myocellular lipid droplets increased in size (0.03 μm2 (0.01–0.06), p < 0.05) and number (0.003 μm−2 (−0.001–0.007), p = 0.09) upon dapagliflozin treatment. CPT1A, CPT1B and malonyl CoA-decarboxylase mRNA expression was increased by dapagliflozin. Fasting acylcarnitine species and C4–OH carnitine levels (0.4704 (0.1246, 0.8162) pmoles∗mg tissue−1, p < 0.001) in skeletal muscle were higher after dapagliflozin treatment, while acetylcarnitine levels were lower (−40.0774 (−64.4766, −15.6782) pmoles∗mg tissue−1, p < 0.001). Fasting levels of several amino acids, succinate, alpha-ketoglutarate and lactate in skeletal muscle were significantly lower after dapagliflozin treatment. ConclusionDapagliflozin treatment for 5 weeks leads to adaptive changes in skeletal muscle substrate metabolism favoring metabolism of fatty acid and ketone bodies and reduced glycolytic flux.The trial is registered with ClinicalTrials.gov, number NCT03338855.

Effect of iron deficiency on skeletal muscle metabolism in heart failure with preserved ejection fraction

Abstract Background Iron deficiency (ID) is suggested to be one of the key comorbidities contributing to heart failure with preserved ejection fraction (HFpEF) and concomitant exercise intolerance, possibly by inducing systemic inflammation and microvascular dysfunction (MVD). ID is associated with poorer prognosis in HFpEF, but its exact impact on exercise capacity in HFpEF patients remains to be further investigated. Purpose To evaluate the effect of ID on exercise capacity in HFpEF patients by assessing skeletal muscle metabolism. Additionally, to assess the association between ID and MVD in HFpEF patients. Methods This prospective study included patients diagnosed with HFpEF according to the ESC Heart Failure 2016 guidelines between January 2018 and May 2021. Patients were excluded if they were of childbearing potential, had any iron supplementation 6 months or chemotherapy 1 year prior to inclusion, were known with significant peripheral artery disease, or had any contraindication for phosphorus-magnetic resonance spectroscopy (31P-MRS). Iron status was defined as absolute ID (serum ferritin &amp;lt;100μg/L), relative ID (serum ferritin 100–299μg/L and transferrin saturation &amp;lt;20%), and no ID. Skeletal muscle oxidative capacity of the upper leg was evaluated by determining phosphocreatine (PCr) recovery kinetics with 31P-MRS in the vastus lateralis muscle after isometric knee extension exercise. Microvascular function was assessed as heat-induced skin hyperemia using laser-Doppler flowmetry. Clinical data up to 6 months prior to or after inclusion was used. Results Twenty-four HFpEF patients without ID and 18 with ID were included, including 14 patients with absolute ID. Clinical characteristics of patients without ID and with ID were comparable: median age 74 [69–79] vs. 77 [69–81] years, 13 (54%) vs. 14 (78%) were females, and 20 (83%) vs. 16 (89%) had a history of hypertension (Table 1). Both groups showed similar halftime of PCr recovery after exercise (29.2 [22.8–33.2] vs. 27.0 [21.1–31.4] seconds, p=0.416), and similar skin hyperaemic flow increase (1142 [576–2247] vs. 1023 [574–1511] %, p=0.554). These measures of skeletal muscle metabolism and microvascular function were not correlated. In a subset of patients (11 without ID and 13 with ID), elevated high-sensitive C-reactive protein (hsCRP) was correlated with PCr recovery halftime in those with ID (R2 0.565, p=0.003). This correlation was not found in patients without ID (R2 0.119, p=0.300) in the original data (Figure 1), but was found after removal of a prominent outlier (R2 0.654, p=0.005). Conclusion HFpEF patients without ID showed comparable skeletal muscle oxidative capacity and microvascular skin hyperaemia compared to HFpEF patients with ID. Post-hoc analysis suggests that inflammation affects skeletal muscle metabolism in HFpEF patients, possibly regardless of ID. Future studies on the effects of ID and inflammation on cellular metabolism could suggest therapeutic targets in HFpEF. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): This study was funded by Vifor Pharma. The funder had no influence on the study results.

In Vivo Muscle Bioenergetics Predict Whole-body Metabolic Responses During A 30-minute Treadmill Walk

While the bioenergetics of working skeletal muscle have been well-studied in humans, the impact of muscle energetic characteristics on the performance of everyday mobility tasks is less clear. PURPOSE: To evaluate the relationships between muscle oxidative and non-oxidative bioenergetic variables, an indicator of muscle substrate use (acetylcarnitine), and whole-body energy metabolism during a standardized mobility activity. METHODS: After obtaining written consent, intramyocellular energetics were measured in vivo in the vastus lateralis of 7 males (mean 28.4 yr, range 25-45) using proton and phosphorus magnetic resonance spectroscopy in response to 2 knee extension protocols: 1) 24 s of maximal isokinetic contractions (0.5 Hz), and 2) 8 min of incremental isotonic contractions (0.5 Hz, 2-min stages at 6, 9, 12, and 15% maximal torque). Continuous measures of ATP production via oxidative phosphorylation, glycolysis and the creatine kinase reaction (CK), and changes in [acetylcarnitine] from pre- to post-contractions, were made. Whole-body metabolic responses to a 30-min treadmill walk (30MTW) at 1.3 m∙s-1 were measured using indirect calorimetry by metabolic cart, from which the rate constant for oxygen (O2) deficit and excess post-exercise oxygen consumption (EPOC), and mean steady state respiratory exchange ratio (RER) were calculated. Spearman rank correlation coefficients (rs) were calculated to evaluate associations between muscle and whole-body metrics. RESULTS: The O2 deficit from the 30MTW was correlated with muscle non-oxidative ATP production by CK (rs = 0.82, p = 0.03) and glycolysis (rs = 0.79, p = 0.05) during the first 2 min of the incremental protocol, as well as with the decrease in [ATP] at the end of the protocol (rs = 0.90, p = 0.01). Muscle [acetylcarnitine] following the incremental protocol was correlated with RER during the 30MTW (rs = 0.81, p = 0.03), and EPOC was related to both non-oxidative ATP production during the incremental protocol (rs = 0.86, p = 0.02), and the rate of phosphocreatine recovery (reflecting oxidative flux) following this protocol (rs = -0.96, p = 0.003). CONCLUSIONS: The results provide novel evidence linking in vivo muscle oxidative and non-oxidative energetics to whole-body metabolic responses during a mobility task relevant to everyday activities.

Muscle Mitochondrial Function And Objective Physical Activity Patterns In Older Adults

PURPOSE: Although age-related declines in mitochondrial function affect physical function, the association between mitochondrial function and accelerometry-derived physical activity—a measurement that summarizes biological, phenotypic, functional, and environmental effects on mobility—remains unclear. This study aimed to characterize the degree to which mitochondrial function is linked to free-living, objectively measured daily physical activity across features of intensity, amount, endurance, and accumulation patterning. METHODS: Data are from 449 participants (mean age 71 years; 55% women) in the Baltimore Longitudinal Study of Aging. Mitochondrial function was measured as skeletal muscle oxidative capacity via post-exercise phosphocreatine recovery rate (τPCr) in the vastus lateralis muscle of the left thigh, using 31P magnetic resonance spectroscopy. Accelerometry was collected by a 7-day, 24-hour wrist-worn protocol. Accelerometer metrics extracted include total activity counts/d (intensity), overall active minutes/d (amount), active minutes/d spent in 5 different bout lengths (endurance; ≥10, ≥20, ≥30, ≥40, ≥50, and ≥ 60 min/day lengths) and activity fragmentation (patterning). Linear regression models were used to estimate the association between τPCr and outcomes of total activity counts, overall minutes spent active, and activity fragmentation. For each bout outcome model, tobit regression was used to account for right skewness. RESULTS: After covariate adjustment, higher τPCr (or slower recovery) was associated with lower total activity counts/d (β = -7118.8, SE = 2394.0; p = 0.003). Conversely, τPCr was not associated with daily active minutes/d (p = 0.11) nor activity fragmentation (p = 0.10). In the bout analysis additionally adjusted for # bouts, τPCr was only associated with time spent in activity bouts lasting ≥60 minutes/d (β = -24.0, SE = 0.12; p = 0.04), which can be considered a biomarker of endurance. CONCLUSIONS: Our results suggest that mitochondrial function is associated with features of intensity and endurance to perform activities lasting ≥60 minutes during everyday physical activity engagement. Our findings help define the connection between laboratory-measured mitochondrial function and real-world physical activity behaviors in older adults.

Chemical Exchange Saturation Transfer Magnetic Resonance Imaging Identifies Abnormal Calf Muscle-Specific Energetics in Peripheral Artery Disease.

Peripheral artery disease (PAD) results in exercise-induced ischemia in leg muscles. 31Phosphorus (P) magnetic resonance spectroscopy demonstrates prolonged phosphocreatine recovery time constant after exercise in PAD but has low signal to noise, low spatial resolution, and requires multinuclear hardware. Chemical exchange saturation transfer (CEST) is a quantitative magnetic resonance imaging method for imaging substrate (CEST asymmetry [CESTasym]) concentration by muscle group. We hypothesized that kinetics measured by CEST could distinguish between patients with PAD and controls. Patients with PAD and age-matched normal subjects were imaged at 3T with a transmit-receive coil around the calf. Four CEST mages were acquired over 24-second intervals. The subjects then performed plantar flexion exercise on a magnetic resonance imaging-compatible ergometer until calf exhaustion. Twenty-five CEST images were obtained at end exercise. Regions of interest were drawn around individual muscle groups, and (CESTasym) decay times were fitted by exponential curve to CEST values. In 10 patients and 11 controls, 31P spectra were obtained 20 minutes later after repeat exercise. Five patients and 5 controls returned at a mean of 1±1 days later for repeat CEST studies. Thirty-five patients with PAD (31 male, age 66±8 years) and 29 controls (11 male, age 63±8 years) were imaged with CEST. The CESTasym decay times for the whole calf (341±332 versus 153±72 seconds; P<0.03) as well as for the gastrocnemius and posterior tibialis were longer in patients with PAD. Agreement between CESTasym decay and phosphocreatine recovery time constant was good. CEST is a magnetic resonance imaging method that can distinguish energetics in patients with PAD from age-matched normal subjects on a per muscle group basis. CEST agrees reasonably well with the gold standard 31P magnetic resonance spectroscopy. Moreover, CEST has higher spatial resolution, creates an image, and does not require multinuclear hardware and thus may be more suitable for clinical studies in PAD.

Assessing the Feasibility of Dynamic 31P Spectroscopy for Metabolic Studies With a 1.0T Extremity Scanner.

The feasibility of conducting in vivo non-localized 31P Magnetic Resonance Spectroscopy (MRS) with a 1.0T extremity scanner and the potential to increase accessibility of this important diagnostic tool for low cost applications is revisited. This work presents a custom transmit-only quadrature birdcage, four-element receive coil array, and spectrometer interfaced to a commercial ONI 1.0T magnet for enabling multi-channel, non-1H frequency capabilities. A custom, magnetic resonance compatible plantar flexion-extension exercise device was also developed to enable exercise protocols. The coils were assessed with bench measurements and 31P phantom studies before an in vivo demonstration. In pulse and acquire spectroscopy of a phantom, the array was found to improve the signal-to-noise ratio (SNR) by a factor of 1.31 and reduce the linewidth by 13.9% when compared to a large loop coil of the same overall size. In vivo testing results show that two averages and a four second repetition time for a temporal resolution of eight seconds was sufficient to obtain phosphocreatine recovery values and baseline pH levels aligned with expected literature values. Initial in vivo human skeletal muscle 31P MRS allowed successful monitoring of metabolic changes during an 18-minute exercise protocol. Adding an array coil and multinuclear capability to a commercial low-cost 1.0T extremity scanner enabled the observation of characteristic 31P metabolic information, such as the phosphocreatinerecovery rate and underlying baseline pH.

1371-P: Dynamic Mapping of Skeletal Muscle Perfusion and Phosphocreatine with 1H Magnetic Resonance Imaging: A Rest-Exercise Study in Diabetes

Aim: Evaluating time and spatially resolved 1H magnetic resonance imaging (MRI) in quantifying muscle tissue phosphocreatine (PCr) kinetics (without extra hardware) and perfusion in healthy individuals and patients with type 2 diabetes mellitus (DM) . Methods: 18 subjects were imaged in 3 groups using a 3T MRI scanner; young healthy (26y, n= 6) , old healthy (62y, n = 6) , and DM patients (66y, n = 6) . For each subject, a chemical exchange saturation transfer (CEST) MRI scan was performed in the calf every 1 min at rest (3 min) , during exercise (4 min standardized isometric plantarflexion) , and a recovery period (6 min) . Subjects also underwent mapping of skeletal muscle perfusion in a separate exercise protocol. PCr concentration maps were quantified by Bloch-McConnell fitting, and values were obtained in the medial gastrocnemius and soleus muscles. Results: DM patients show a longer PCr recovery time τ during recovery compared to both healthy groups: young healthy τ = 47.1 ± 18.2s, old healthy τ = 41.9 ± 15.1s, and DM τ =122.2 ± 58.6s, p = 0.02 (Figure) . There is a negative correlation between PCr and perfusion during exercise in healthy groups (r = 0.38, p = 0.034) that is not significant in the DM group. Conclusion: Dynamic PCr mapping by proton MRI in calf muscle reveals impaired energetics that is uncoupled from muscle perfusion in DM compared to healthy controls. Disclosure R.Wahidi: None. R.Li: None. M.A.Zayed: None. M.Hastings: None. J.Zheng: None.

Ankle-Brachial Index and Energy Production in People Without Peripheral Artery Disease: The BLSA.

BackgroundLower ankle‐brachial index (ABI) values within the 0.90 to 1.40 range are associated with poorer mitochondrial oxidative capacity of thigh muscles in cross‐sectional analyses. Whether ABI decline is associated with greater declines in thigh muscle oxidative capacity with aging is unknown.Method and ResultsWe analyzed data from 228 participants (100 men) of the BLSA (Baltimore Longitudinal Study of Aging), aged 39 to 97 years, with an ABI between 0.9 and 1.40 at baseline and at follow‐up (mean follow‐up period of 2.8 years). We examined mitochondrial oxidative capacity of the left thigh muscle, by measuring the postexercise phosphocreatine recovery rate constant (kPCr) from phosphorus‐31 magnetic resonance spectroscopy. Greater kPCr indicated higher mitochondrial oxidative capacity. Although kPCr was available on the left leg only, ABI was measured in both legs. Longitudinal rates of change (Change) of left and right ABI and kPCr of the left thigh muscle were estimated using linear mixed effects models, and their association was analyzed by standardized multiple linear regressions. In multivariate analysis including sex, age, baseline kPCr, both left and right baseline ABI, and ABI change in both legs, (kPCr)Change was directly associated with ipsilateral (left) (ABI)Change (standardized [STD]‐β=0.14; P=0.0168) but not with contralateral (right) (ABI)Change (P=0.22). Adjusting for traditional cardiovascular risk factors, this association remained significant (STD‐β=0.18; P=0.0051). (kPCr)Change was steeper in White race participants (STD‐β=0.16; P=0.0122) and body mass index (STD‐β=0.13; P=0.0479). There was no significant association with current smoking status (P=0.63), fasting glucose (P=0.28), heart rate (P=0.67), mean blood pressure (P=0.78), and low‐density lipoprotein (P=0.75), high‐density lipoprotein (P=0.82), or triglycerides (P=0.15).ConclusionsIn people without peripheral arterial disease, greater decline in ABI over time, but not baseline ABI, was associated with faster decline in thigh mitochondrial oxidative capacity in the ipsilateral leg. Further studies are needed to examine whether early interventions that improve lower extremity muscle perfusion can improve and prevent the decline of muscle energetics.

P062 31P MRS and MRI phenotyping of muscle metabolic quality in IBD fatigue

Abstract Background Fatigue perception and exercise intolerance are common in inflammatory bowel disease (IBD). The mechanisms are unknown, although physical deconditioning is greater in fatigued relative to non-fatigued patients, suggesting an aetiological role for deconditioning. To assess peripheral muscle quality in Crohn’s disease (CD), we quantified the time-course of muscle phosphocreatine (PCr) recovery, which is wholly mitochondrial dependent, following ischaemic high-intensity exercise in fatigued CD and HV. Methods Participant body mass and regional body composition was assessed by DEXA. All MR data was collected using a 3T Philips Achieva scanner and a 14cm 31P coil on the medial gastrocnemius muscle. 1H mDIXON scans were acquired to image the calf prior to ischaemic plantar flexion exercise at 50% maximum voluntary contraction (MVC) using an MR-compatible ergometer (Trispect, Ergospect) during non-localized pulse-acquire 31P-MRS. 31P spectra were analysed using jMRUI Beta 6.0 using the AMARES function with prior knowledge. Cytosolic pH was estimated using the chemical shift difference between Pi and PCr peaks. Post exercise PCr recovery was quantified after reinstating limb blood flow. PCr recovery was expressed relative to baseline (non-ischaemic) signal amplitude and fit to a mono-exponential function in GraphPad prism. (PCr(t) = PCrinitial+(PCrend – PCrinitial)(1-exp(-k.t)) where t is the time from the start of non-ischaemic recovery, PCrinitial and PCrend is the PCr signal at the initial and end of recovery phases. An FSL and Matlab pipeline was used to obtain calf muscle volume and fat fraction from 1H mDIXON images. Results 13 quiescent CD patients (7 female, HBI 1±2, CRP &amp;lt;5) and 9 HVs (4 female) were matched for age (P = 0.986) and BMI (P = 0.845). General fatigue score was greater in CD (13 ± 4) relative to HV (8 ± 3) (t19=3.08, P = 0.006) (Table 1.) End-exercise muscle PCr depletion (%) (85.25 ± 10.12 vs 83.28 ± 7.8%, P = 0.639) and estimated end-exercise muscle pH (6.6 ± 0.2 vs 6.5 ± 0.2, P = 0.320) was consistent between HV and CD. The mean rate constant of PCr resynthesis (kPCr min-1) in CD (0.76 ± 0.23) was significantly less (t20 = 2.6, P = 0.016) than HV (1.03 ± 0.23). PCr recovery curves were well described using a mono-exponential function in CD (R2=0.98 ± 0.01, R2value) and HV (R2=0.96 ± 0.03) (Table 3). Conclusion The PCr resynthesis rate following intensity matched ischemic exercise was less in fatigued CD patients relative to HV. This points to peripheral muscle deconditioning and associated loss of mitochondrial mass as a driver of exercise intolerance in IBD. This may be amenable to exercise training intervention.

Abstract 12812: Creatine Chemical Exchange Transfer MRI Demonstrates Abnormal Calf Muscle Energetics in Peripheral Arterial Disease

Introduction: Creatine chemical exchange saturation transfer (CrCEST) is a novel MRI technique utilizing radiofrequency pulses to monitor creatine concentrations at high spatial resolution. The study utilized CrCEST kinetics to compare post-exercise creatine decay in peripheral arterial disease (PAD) patients to normal subjects and to validate against phosphocreatine (PCr) recovery by 31 phosphorus (P) MR spectroscopy (MRS). Methods: 23 subjects with PAD (claudication and ankle-brachial index&lt;0.9) and 28 healthy subjects were enrolled. All underwent 3T MRI (Siemens Prisma) using a knee coil around the calf. Pre- and post-exercise images were obtained around plantar flexion ergometry (Ergospect) until exhaustion. Regions of interests were drawn around major muscle groups. Creatine decay times were obtained by fitting an exponential curve to the CrCEST values. 31 P spectra were obtained 20 minutes later at peak exercise using a surface-coil localized, free induction decay acquisition with 25 signal averages at a repetition time of 550s with calculation of PCr recovery time constant. Results: 23 PAD subjects (mean ABI 0.66 ± 0.11, age 64 ± 8, 17% females) had prolonged median overall calf muscle creatine decay time of 286 seconds (s) (Interquartile Range (IQR) 134 to 370) versus 152 s (IQR 114 to 193) in controls (age 63 ± 9, 70% females), p = 0.009. The gastrocnemius muscle demonstrated a creatine decay time of 316 s in PAD (IQR 189 to 510) versus 181 s in controls (IQR 102 to 236), p = 0.003 and the posterior tibialis muscle, 186 s (IQR 119 to 653) versus 125 s (IQR 72 to 221), p = 0.013. 8 PAD patients and 6 controls underwent CrCEST and 31 P MRS which were compared over the entire calf. Bland-Altman analysis (Figure 1B) yielded a mean difference of 71s (SD 109). Conclusions: Imaging with CrCEST demonstrates prolonged creatine kinetics in PAD patients compared to normal subjects with high spatial resolution and good agreement with 31 P MRS, although PCr recovery appears faster.

Lower extremity MRI following 10-week supervised exercise intervention in patients with diabetic peripheral neuropathy

IntroductionThe purpose of this study was to characterize using MRI the effects of a 10-week supervised exercise program on lower extremity skeletal muscle composition, nerve microarchitecture, and metabolic function in...