Phosphocreatine Recovery Time Constant Research Articles

Cyclosporine A Delays the Terminal Disease Stage in the Tfam KO Mitochondrial Myopathy Mouse Model Without Improving Mitochondrial Energy Production.

Mitochondrial myopathies are rare genetic disorders for which no effective treatment exists. We previously showed that the pharmacological cyclophilin inhibitor cyclosporine A (CsA) extends the lifespan of fast-twitch skeletal muscle-specific mitochondrial transcription factor A knockout (Tfam KO) mice, lacking the ability to transcribe mitochondrial DNA and displaying lethal mitochondrial myopathy. Our present aim was to assess whether the positive effect of CsA was associated with improved invivo mitochondrial energy production. Mice were treated with CsA for 4 weeks, beginning at 12 weeks (i.e., before the terminal disease phase). Hindlimb plantar flexor muscles were fatigued by 80 contractions (40 Hz, 1.5 s on, 6 s off) while measuring force and energy metabolism using phosphorus-31 magnetic resonance spectroscopy. Force decreased at similar rates in Tfam KO mice with and without the CsA treatment, reaching 50% of the baseline value after ~14 ± 1 contractions, which was faster than in control mice (25 ± 1 contractions). Phosphocreatine (PCr) decreased to ~10% of the control concentration in Tfam KO mice, independent of the treatment, which was larger than the ~20% observed in control mice. The time constant of PCr recovery was higher in untreated Tfam KO than that in control muscle (+100%) and similar in untreated and CsA-treated Tfam KO mice. The results do not support improved mitochondrial energy production as a mechanism underlying the prolonged lifespan of Tfam KO mitochondrial myopathy mice treated with CsA. Thus, other mechanisms must be involved, such as the previously observed CsA-mediated protection against excessive mitochondrial Ca2+ accumulation.

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.

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.

Greater Skeletal Muscle Oxidative Capacity Is Associated With Higher Resting Metabolic Rate: Results From the BLSA

Resting metabolic rate (RMR) tends to decline with aging. The age-trajectory of decline in RMR is similar to changes that occur in muscle mass, muscle strength and fitness. However, while the decline in these phenotypes have been related to changes of mitochondrial function and oxidative capacity, whether lower RMR is associated with poorer mitochondrial oxidative capacity is unknown. In 619 participants of the Baltimore Longitudinal Study of Aging, we analyzed the cross-sectional association between RMR (kcal/day), assessed by indirect calorimetry, and skeletal muscle maximal oxidative phosphorylation capacity, assessed as post-exercise phosphocreatine recovery time constant (tau-PCr), by phosphorous magnetic resonance spectroscopy. Linear regression models were used to evaluate the relationship between tau-PCr and RMR, adjusting for potential confounders. We found that independent of age, sex, lean body mass, muscle density and fat mass, higher RMR was significantly associated with shorter tau-PCr, indicating greater mitochondrial oxidative capacity. In conclusion, higher RMR appears to be associated with a higher mitochondrial oxidative capacity in skeletal muscle. This association may reflect a relationship between better muscle quality and greater mitochondrial health.

A Plasma Proteomic Signature of Skeletal Muscle Mitochondrial Function.

Although mitochondrial dysfunction has been implicated in aging, physical function decline, and several age-related diseases, an accessible and affordable measure of mitochondrial health is still lacking. In this study we identified the proteomic signature of muscular mitochondrial oxidative capacity in plasma. In 165 adults, we analyzed the association between concentrations of plasma proteins, measured using the SOMAscan assay, and skeletal muscle maximal oxidative phosphorylation capacity assessed as post-exercise phosphocreatine recovery time constant (τPCr) by phosphorous magnetic resonance spectroscopy. Out of 1301 proteins analyzed, we identified 87 proteins significantly associated with τPCr, adjusting for age, sex, and phosphocreatine depletion. Sixty proteins were positively correlated with better oxidative capacity, while 27 proteins were correlated with poorer capacity. Specific clusters of plasma proteins were enriched in the following pathways: homeostasis of energy metabolism, proteostasis, response to oxidative stress, and inflammation. The generalizability of these findings would benefit from replication in an independent cohort and in longitudinal analyses.

Cardiovascular Health and Mitochondrial Function: Testing an Association.

Although mitochondrial dysfunction appears to be a contributing factor in the pathogenesis of cardiovascular and metabolic diseases, empirical data on this association are still lacking. This study evaluated whether mitochondrial oxidative capacity, as assessed by phosphorus magnetic resonance spectroscopy, was associated with cardiovascular risk, as estimated by the Framingham Risk Score (FRS), and with a clinical history of cardiovascular disease (CVD), in community-dwelling adults. A total of 616 subjects from the Baltimore Longitudinal Study of Aging (mean age 66 years) underwent a comprehensive clinical evaluation. Mitochondrial oxidative capacity in skeletal muscle was assessed as post-exercise phosphocreatine recovery time constant by phosphorus magnetic resonance spectroscopy. Multivariate regression models were employed to determine the cross-sectional association of mitochondrial oxidative capacity with FRS and history of CVD. Decreased mitochondrial oxidative capacity was strongly associated with higher FRS independent of age, body composition, and physical activity. Lower oxidative capacity was also associated with a history of positive of CVD and higher number of CVD events. We speculate that the observed association could reflect the effect of an excessive production of oxidative species by dysfunctional mitochondria. Furthermore, decreased energy production could hamper the functionality of heart and vessels. In turn, a malfunctioning cardiovascular apparatus could fail to deliver the oxygen necessary for optimal mitochondrial energy production, therefore creating a vicious cycle. Longitudinal studies are necessary to ascertain the directionality of the association and the eventual presence of common pathogenetic roots. In conclusion, mitochondria could represent an important target for intervention in cardiovascular health.

Statin Therapy Does Not Limit Improvements In Mitochondrial Function And Cardiorespiratory Fitness Following Moderate Exercise

INTRODUCTION: Statin medications are widely used to reduce major cardiovascular risk factors and events, but have also been reported to reduce cardiorespiratory and mitochondrial adaptations expected with aerobic exercise training. The current study evaluated the influence of statin therapy on aerobic exercise training adaptations in older adults. METHODS: Twenty-eight healthy, sedentary older adults (67±5 yrs old, BMI=30±5, mean±SD, 5 males) participated in a 12-week randomized graded treadmill walking intervention (EX) with roughly half the group on statin therapy (+statin). 31P MRS was used to quantify oxidative capacity of the plantar flexor muscles (3T MRI, 51.7MHz, TR=3s); a monoexponential model was used to fit the time constant of phosphocreatine recovery following acute plantar flexion. Peak oxygen consumption (VO2 peak) was measured during a modified Balke exercise stress test. Repeated measures ANOVA was used to assess changes in muscle oxidative capacity and VO2 peak between groups with significance at p<0.05. RESULTS: Prior to the exercise intervention, PCr time constant (tau, s) was significantly prolonged in statin users (+statin 42.2±10.5s; -statin =34.1±9.9s; p=0.039). Following exercise training, the time constant was reduced by 27% (Pre: 40.3±29.6s; Post: 29.6±10.4s) for EX compared to CON (Pre: 35.5±6.3s to 36.4±9.0s), p=0.001, n=27. There was no significant effect of statin therapy with a 28.0% improvement for EX+statin compared to a 25.3% for EX-statin. VO2 peak increased 11% following EX (Pre:18.8±2.8 ml/kg/min, Post: 20.1±3.5 ml/kg/min) compared to CON (Pre: 21.8±3.7, Post: 20.8±3.6 ml/kg/min), p=0.001, n=21 with no effect of statin therapy. CONCLUSION: Moderate exercise training in older adults on a low dose statin resulted in typical increases in aerobic fitness. These results are encouraging for the majority of older adults as 50% or more are likely to be prescribed a statin for reduction in cardiovascular event risk or prevention of metabolic syndrome. Supported by NIH AG042041.

Multinuclear MRS at 7T Uncovers Exercise Driven Differences in Skeletal Muscle Energy Metabolism Between Young and Seniors.

Purpose: Aging is associated with changes in muscle energy metabolism. Proton (1H) and phosphorous (31P) magnetic resonance spectroscopy (MRS) has been successfully applied for non-invasive investigation of skeletal muscle metabolism. The aim of this study was to detect differences in adenosine triphosphate (ATP) production in the aging muscle by 31P-MRS and to identify potential changes associated with buffer capacity of muscle carnosine by 1H-MRS.Methods: Fifteen young and nineteen elderly volunteers were examined. 1H and 31P-MRS spectra were acquired at high field (7T). The investigation included carnosine quantification using 1H-MRS and resting and dynamic 31P-MRS, both including saturation transfer measurements of phosphocreatine (PCr), and inorganic phosphate (Pi)-to-ATP metabolic fluxes.Results: Elderly volunteers had higher time constant of PCr recovery (τPCr) in comparison to the young volunteers. Exercise was connected with significant decrease in PCr-to-ATP flux in both groups. Moreover, PCr-to-ATP flux was significantly higher in young compared to elderly both at rest and during exercise. Similarly, an increment of Pi-to-ATP flux with exercise was found in both groups but the intergroup difference was only observed during exercise. Elderly had lower muscle carnosine concentration and lower postexercise pH. A strong increase in phosphomonoester (PME) concentration was observed with exercise in elderly, and a faster Pi:PCr kinetics was found in young volunteers compared to elderly during the recovery period.Conclusion: Observations of a massive increment of PME concentration together with high Pi-to-ATP flux during exercise in seniors refer to decreased ability of the muscle to meet the metabolic requirements of exercise and thus a limited ability of seniors to effectively support the exercise load.

Skeletal Muscle Mitochondrial Dysfunction Is Present in Patients with CKD before Initiation of Maintenance Hemodialysis.

Patients with CKD suffer from frailty and sarcopenia, which is associated with higher morbidity and mortality. Skeletal muscle mitochondria are important for physical function and could be a target to prevent frailty and sarcopenia. In this study, we tested the hypothesis that mitochondrial dysfunction is associated with the severity of CKD. We also evaluated the interaction between mitochondrial function and coexisting comorbidities, such as impaired physical performance, intermuscular adipose tissue infiltration, inflammation, and oxidative stress. Sixty-three participants were studied, including controls (n=21), patients with CKD not on maintenance hemodialysis (CKD 3-5; n=20), and patients on maintenance hemodialysis (n=22). We evaluated in vivo knee extensors mitochondrial function using 31P magnetic resonance spectroscopy to obtain the phosphocreatine recovery time constant, a measure of mitochondrial function. We measured physical performance using the 6-minute walk test, intermuscular adipose tissue infiltration with magnetic resonance imaging, and markers of inflammation and oxidative stress in plasma. In skeletal muscle biopsies from a select number of patients on maintenance hemodialysis, we also measured markers of mitochondrial dynamics (fusion and fission). We found a prolonged phosphocreatine recovery constant in patients on maintenance hemodialysis (53.3 [43.4-70.1] seconds, median [interquartile range]) and patients with CKD not on maintenance hemodialysis (41.5 [35.4-49.1] seconds) compared with controls (38.9 [32.5-46.0] seconds; P=0.001 among groups). Mitochondrial dysfunction was associated with poor physical performance (r=0.62; P=0.001), greater intermuscular adipose tissue (r=0.44; P=0.001), and increased markers of inflammation and oxidative stress (r=0.60; P=0.001). We found mitochondrial fragmentation and increased content of dynamin-related protein 1, a marker of mitochondrial fission, in skeletal muscles from patients on maintenance hemodialysis (0.86 [0.48-1.35] arbitrary units (A.U.), median [interquartile range]) compared with controls (0.60 [0.24-0.75] A.U.). Mitochondrial dysfunction is due to multifactorial etiologies and presents prior to the initiation of maintenance hemodialysis, including in patients with CKD stages 3-5.

Poor mitochondrial health and systemic inflammation? Test of a classic hypothesis in the Baltimore Longitudinal Study of Aging.

Although a persistent inflammatory state has long been associated with aging and negative health outcomes, the underlying mechanisms remain unclear. Mitochondrial dysfunction has been proposed as a cause of inflammaging, but evidence of an association in humans is lacking. In this study, we analyzed the cross-sectional association between inflammatory biomarkers and mitochondrial oxidative capacity in skeletal muscle, assessed as post-exercise phosphocreatine recovery time constant by phosphorus magnetic resonance spectroscopy, in a population of 669 adults (mean age 67years) from the Baltimore Longitudinal Study of Aging. We observed that participants with lower mitochondrial oxidative capacity exhibited hallmarks of inflammation, specifically markedly higher levels of interleukin-6 and C-reactive protein, as well as increased erythrocyte sedimentation rate when compared with participants with better oxidative capacity, independent of age and sex. We speculate that this association reflects the observation that products of damaged mitochondria, such as mitochondrial DNA, activate multiple pathways that lead to inflammation. Furthermore, excess production of oxidative species (ROS) by dysfunctional mitochondria could trigger inflammation either directly via NF-κB or through oxidative damage to proteins, lipids, and nucleic acids. Longitudinal studies are necessary to ascertain whether and through which mechanisms mitochondrial dysfunction activate inflammation or whether both these phenomena derive from a common root.

Greater Skeletal Muscle Oxidative Capacity Is Associated With Higher Resting Metabolic Rate: Results From the Baltimore Longitudinal Study of Aging.

Resting metabolic rate (RMR) tends to decline with aging. The age-trajectory of decline in RMR is similar to changes that occur in muscle mass, muscle strength, and fitness, but while the decline in these phenotypes has been related to changes of mitochondrial function and oxidative capacity, whether lower RMR is associated with poorer mitochondrial oxidative capacity is unknown. In 619 participants of the Baltimore Longitudinal Study of Aging, we analyzed the cross-sectional association between RMR (kcal/day), assessed by indirect calorimetry, and skeletal muscle maximal oxidative phosphorylation capacity, assessed as postexercise phosphocreatine recovery time constant (τ PCr), by phosphorous magnetic resonance spectroscopy. Linear regression models were used to evaluate the relationship between τ PCr and RMR, adjusting for potential confounders. Independent of age, sex, lean body mass, muscle density, and fat mass, higher RMR was significantly associated with shorter τ PCr, indicating greater mitochondrial oxidative capacity. Higher RMR is associated with a higher mitochondrial oxidative capacity in skeletal muscle. This association may reflect a relationship between better muscle quality and greater mitochondrial health.

Dynamic magnetic resonance measurements of calf muscle oxygenation and energy metabolism in peripheral artery disease.

BackgroundClinical assessments of peripheral artery disease (PAD) severity are insensitive to pathophysiological changes in muscle tissue oxygenation and energy metabolism distal to the affected artery.PurposeTo quantify the blood oxygenation level‐dependent (BOLD) response and phosphocreatine (PCr) recovery kinetics on a clinical MR system during a single exercise‐recovery session in PAD patients.Study TypeCase–control study.SubjectsFifteen Fontaine stage II patients, and 18 healthy control subjectsField Strength/SequenceInterleaved dynamic multiecho gradient‐echo 1H T2* mapping and adiabatic pulse‐acquire 31P‐MR spectroscopy at 3T.AssessmentBlood pressure in the arms and ankles were measured to determine the ankle‐brachial index (ABI). Subjects performed a plantar flexion exercise‐recovery protocol. The gastrocnemius and soleus muscle BOLD responses were characterized using the T2* maps. High‐energy phosphate metabolite concentrations were quantified by fitting the series of 31P‐MR spectra. The PCr recovery time constant (τPCr) was derived as a measure of in vivo mitochondrial oxidative capacity.Statistical TestsComparisons between groups were performed using two‐sided Mann–Whitney U‐tests. Relations between variables were assessed by Pearson's r correlation coefficients.ResultsThe amplitude of the functional hyperemic BOLD response in the gastrocnemius muscle was higher in PAD patients compared with healthy subjects (–3.8 ± 1.4% vs. –1.4 ± 0.3%; P < 0.001), and correlated with the ABI (r = 0.79; P < 0.001). PCr recovery was slower in PAD patients (τPCr = 52.0 ± 13.5 vs. 30.3 ± 9.7 sec; P < 0.0001), and correlated with the ABI (r = –0.64; P < 0.001). Moreover, τPCr correlated with the hyperemic BOLD response in the gastrocnemius muscle (r = –0.66; P < 0.01).Data ConclusionMR readouts of calf muscle tissue oxygenation and high‐energy phosphate metabolism were acquired essentially simultaneously during a single exercise‐recovery session. A pronounced hypoxia‐triggered vasodilation in PAD is associated with a reduced mitochondrial oxidative capacity. Level of Evidence: 2 Technical Efficacy: Stage 1 J. Magn. Reson. Imaging 2020;51:98–107.

Mitochondrial Bioenergetic Metabolism Is Associated with Total Body Composition and Influenced by Normal Weight Obesity (P21-039-19)

ObjectivesObesity, body composition, and mitochondrial dysfunction play important roles in the development of metabolic diseases, but it is unknown if increased visceral fat (VF) specifically alters mitochondrial bioenergetic capacity. We determined whether in vivo and ex vivo bioenergetic indexes are associated with total body composition, visceral fat (VF), and body composition subtypes. MethodsThis pilot study included 34 healthy adults (56% female, median age 27.9 y). Body composition and fat distribution were assessed by dual energy x-ray absorptiometry. Subjects were categorized as lean (BMI < 25 kg/m2, n = 14), normal weight obese (NWO, BMI < 25 kg/m2 and >30% body fat in women or >23% body fat in men, n = 8), or overweight/obese (O/O, BMI > 25 kg/m2, n = 12). Ex vivo mitochondrial function was assessed using a Seahorse extracellular flux analyzer in peripheral blood mononuclear cells (PBMC) and isolated monocytes. In a subset (n = 21), maximum in vivo ATP synthesis was assessed in the quadriceps using 31P-Magnetic resonance spectroscopy based on the phosphocreatine recovery time constant (τPCr) following a standardized leg exercise. Statistical analyses included Spearman correlations and Kruskal-Wallis tests. ResultsIn monocytes, but not PBMCs, % spare respiratory capacity was inversely associated with % body fat (r = −0.42, P = 0.02) and positively associated with lean body mass (r = 0.36, P = 0.04) but was not significantly associated with VF. Skeletal muscle τPCr was positively associated with % body fat (r = 0.58, P < 0.01) and total body fat (r = 0.53, P = 0.02) but not VF. Subjects with NWO had the highest τPCr (P = 0.01) and lowest % spare respiratory capacity (P = 0.09 and 0.03 in monocytes and PBMCs, respectively) compared to lean or O/O subjects. ConclusionsTotal body fat, but not VF, was associated with impaired mitochondrial function as shown by increased post-exercise recovery time in skeletal muscle and decreased response to energy demands in circulating cells. Adults with NWO had worse bioenergetic capacity than O/O or lean adults. These data provide insight on the relationships between human body composition and mitochondrial energy metabolism, which plays a role in metabolic disease progression. Funding SourcesNational Institutes of Health, Georgia Clinical and Translational Science Alliance.

1935-P: Decoupling between ATP Utilization and Replenishment in Insulin Resistant Skeletal Muscle

For optimal energy utilization, depletion and recovery of phosphocreatine (PCr) during exercise must be tightly coupled. Aim: To measure metabolites in vastus lateralis (VL) muscle of normal glucose tolerant (NGT) and type 2 diabetes mellitus (T2DM) subjects by phosphorus-31 magnetic resonance spectroscopy (31P-MRS) during and following exercise. Matsuda index (MI) of insulin sensitivity, fasting plasma glucose (FPG), intramyocellular lipid concentration [IMCL], and mitochondrial density (MitoD) were also measured. Methods: 12 NGT (age=50±11y; A1c=5.6±0.3%; BMI=28.5±4.1kg/m-2) and 10 T2DM (age=53±10y; A1c=7.5±0.8%; BMI=30.4±4.6kg/m-2) subjects received an OGTT to determine MI. [IMCL] in VL was quantified by 1H-MRS. In 15 subjects (7 T2DM, 8 NGT) MitD was determined by electron microscopy. Results: The PCr recovery time constant (k) was lower in T2DM (0.01±0.004 vs. 0.02±0.01 s-1; p=0.05). Baseline [PCr] (25.3±3.0 vs. 28.5±3.3 mM; p=0.03) and average [PCr] over the last minute of exercise (14.5±4.7 vs. 20.9±4.7 mM; p&amp;lt;0.05) were lower in T2DM. PCr percent decrease, (%Δ), was negatively correlated with PCr recovery halftime, t (ρ=0.77; p&amp;lt;0.05). The initial rate of PCr depletion and initial rate of PCr recovery were correlated in NGT (r=0.83; p&amp;lt;0.05) but not in T2DM subjects (r=0.30; p=0.39). FPG negatively correlated with baseline [PCr] (ρ=-0.63; p&amp;lt;0.05) and MI negatively correlated with %Δ (ρ=-0.50; p&amp;lt;0.05) in all subjects. [IMCL] was increased in T2DM (6.9±1.2 vs. 9.1±1.4; p&amp;lt;0.05) and correlated negatively with t (ρ=0.47; p=0.03). MitoD in T2DM subjects correlated with k (r=0.76; p&amp;lt;0.05). Conclusion: These data suggest a disruption in the regulation of energy utilization and production of ATP and PCr, which may be due to reduced mitochondrial density and/or altered substrate dynamics in T2DM skeletal muscle. Disclosure J.A. Vasquez: None. C. Solis-Herrera: Advisory Panel; Self; Sanofi. D. Tripathy: None. M. Abdul-Ghani: None. R.A. DeFronzo: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Elcelyx Therapeutics, Inc., Intarcia Therapeutics, Inc., Janssen Pharmaceuticals, Inc., Novo Nordisk Inc. Research Support; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Janssen Pharmaceuticals, Inc., Merck &amp; Co., Inc. Speaker's Bureau; Self; AstraZeneca, Novo Nordisk Inc. G.D. Clarke: None. Funding National Institutes of Health (DK-24092-34 to R.A.D), (K25-DK-089012 to G.D.C.)

Differences in Muscle Metabolism Between Triathletes and Normally Active Volunteers Investigated Using Multinuclear Magnetic Resonance Spectroscopy at 7T.

Purpose: The influence of endurance training on skeletal muscle metabolism can currently be studied only by invasive sampling or through a few related parameters that are investigated by either proton (1H) or phosphorus (31P) magnetic resonance spectroscopy (MRS). The aim of this study was to compare the metabolic differences between endurance-trained triathletes and healthy volunteers using multi-parametric data acquired by both, 31P- and 1H-MRS, at ultra-high field (7T) in a single experimental protocol. This study also aimed to determine the interrelations between these MRS-derived metabolic parameters.Methods: Thirteen male triathletes and ten active male volunteers participated in the study. Proton MRS data from the vastus lateralis yielded concentrations of acetylcarnitine, carnosine, and intramyocellular lipids (IMCL). For the measurement of phosphodiesters (PDEs), inorganic phosphate (Pi), phosphocreatine (PCr), and maximal oxidative capacity (Qmax) phosphorus MRS data were acquired at rest, during 6 min of submaximal exercise and following immediate recovery.Results: The triathletes exhibited significantly higher IMCL levels, higher initial rate of PCr resynthesis (VPCr) during the recovery period, a shorter PCr recovery time constant (τPCr), and higher Qmax. Multivariate stepwise regression analysis identified PDE as the strongest independent predictor of whole-body maximal oxygen uptake (VO2max).Conclusion: In conclusion, we cannot suggest a single MRS-based parameter as an exclusive biomarker of muscular fitness and training status. There is, rather, a combination of different parameters, assessable during a single multi-nuclear MRS session that could be useful for further cross-sectional and/or focused interventional studies on skeletal muscle fitness and training effects.

Insulin Resistance Is Associated With Reduced Mitochondrial Oxidative Capacity Measured by 31P-Magnetic Resonance Spectroscopy in Participants Without Diabetes From the Baltimore Longitudinal Study of Aging

Whether individuals with insulin resistance (IR) but without criteria for diabetes exhibit reduced mitochondrial oxidative capacity is unclear; addressing this question could guide research for new therapeutics. We investigated 248 participants without diabetes from the Baltimore Longitudinal Study of Aging (BLSA) to determine whether impaired mitochondrial capacity is associated with prediabetes, IR, and duration and severity of hyperglycemia exposure. Mitochondrial capacity was assessed as the postexercise phosphocreatine recovery time constant (τPCr) by 31P-magnetic resonance spectroscopy, with higher τPCr values reflecting reduced capacity. Prediabetes was defined using the American Diabetes Association criteria from fasting and 2-h glucose measurements. IR and sensitivity were calculated using HOMA-IR and Matsuda indices. The duration and severity of hyperglycemia exposure were estimated as the number of years from prediabetes onset and the average oral glucose tolerance test (OGTT) 2-h glucose measurement over previous BLSA visits. Covariates included age, sex, body composition, physical activity, and other confounders. Higher likelihood of prediabetes, higher HOMA-IR, and lower Matsuda index were associated with longer τPCr. Among 205 participants with previous OGTT data, greater severity and longer duration of hyperglycemia were independently associated with longer τPC. In conclusion, in individuals without diabetes a more impaired mitochondrial capacity is associated with greater IR and a higher likelihood of prediabetes.

Mitochondrial function assessed by 31P MRS and BOLD MRI in non-obese type 2 diabetic rats.

The study aims to characterize age‐associated changes in skeletal muscle bioenergetics by evaluating the response to ischemia‐reperfusion in the skeletal muscle of the Goto‐Kakizaki (GK) rats, a rat model of non‐obese type 2 diabetes (T2D). 31P magnetic resonance spectroscopy (MRS) and blood oxygen level‐dependent (BOLD) MRI was performed on the hindlimb of young (12 weeks) and adult (20 weeks) GK and Wistar (control) rats. 31P‐MRS and BOLD‐MRI data were acquired continuously during an ischemia and reperfusion protocol to quantify changes in phosphate metabolites and muscle oxygenation. The time constant of phosphocreatine recovery, an index of mitochondrial oxidative capacity, was not statistically different between GK rats (60.8 ± 13.9 sec in young group, 83.7 ± 13.0 sec in adult group) and their age‐matched controls (62.4 ± 11.6 sec in young group, 77.5 ± 7.1 sec in adult group). During ischemia, baseline‐normalized BOLD‐MRI signal was significantly lower in GK rats than in their age‐matched controls. These results suggest that insulin resistance leads to alterations in tissue metabolism without impaired mitochondrial oxidative capacity in GK rats.

SU‐F‐I‐25: Reproducibility of Phosphorus MRS and Work Measurements for Evaluating Skeletal Muscle Metabolism

Purpose:Skeletal muscle energetics were studied by phosphorus‐31 MRS (31P‐MRS) during exercise. The reproducibility of work performed and the MRS parameters were investigated.Methods:Reproducibility of the 31P‐MRS exercise parameters was validated in five healthy volunteers (2 M/3 F, age 39.2 ± 21.9 yr, BMI 25.1 ± 4.8 kg/m2). Five minute exercise of the vastus lateralis (VL) was performed on two separate occasions during MRS in a 3 Tesla MRI system. The exercise (up to 13.5 kg resistance) was measured on a strain gage. The summation of force applied (strain level) over time (Δt = 20 ms) was taken as the work output. The phosphocreatine (PCr) recovery time constant (k) following exercise was determined from nonlinear least squares fitting of MRS spectra acquired every 3 s to the Levenberg‐Marquardt equation. Maximum oxidative capacity was calculated from the baseline [PCr] and k, as previously described. The protocol was approved by the IRB.Results:The percent drop of PCr = 40.7 ± 13.4% and the rate of PCr recovery was 0.16 ± 0.03 mM•s−1 (k = 0.018 ± 0.003 s−1). The mean recovery time, τ, of PCr was 40.0 ± 8.1 s, which corresponds well with current literature values in healthy subjects (32 ± 3 s to 53 ± 25 s). Bland‐Altman analysis showed poor reproducibility (LOA ratio = 55.7) in work performed h, the k‐value for PCr was very reproducible (bias = −1.28*10−4, random error = 3.32*10−3). The % drop in PCr was negatively but significantly correlated with the oxidative phosphorylation capacity (r= −0.84, p=0.003).Conclusion:[PCr] changes during VL exercise and recovery were reproducible and not affected by inconsistent work being performed during exercise bouts. The results suggest that this system should be useful for relating work vs. metabolism differences between subjects with differing metabolic profiles.

Phosphocreatine recovery time constant (PCr) at peak exercise as a potential endpoint for clinical trials in PAD

Phosphocreatine recovery time constant (PCr) at peak exercise as a potential endpoint for clinical trials in PAD

Once-weekly muscle endurance and strength training prevents deterioration of muscle oxidative function and attenuates the degree of strength decline during 3-week forearm immobilization.

Muscle unloading causes muscle function deterioration, but the extent to which training frequency or volume can be reduced while preserving muscle function during muscle unloading is unknown. We examined the effects of low-volume muscle endurance and strength training on forearm muscle oxidative capacity, endurance, and strength during a 3-week immobilization. Twenty-seven, healthy, male volunteers were divided into four groups: immobilization only (IMM); immobilization with endurance and strength training, once-weekly (IMM + EST1) or twice-weekly (IMM + EST2); and control, without immobilization or training (CNT). Endurance training involved dynamic handgrip exercise, at 30% of maximal voluntary contraction (MVC), until exhaustion (~60 s). Strength training involved intermittent isometric handgrip exercise at 70% MVC (40 s). Muscle oxidative capacity was evaluated after exercise using the phosphocreatine recovery time constant using (31)phosphorus magnetic resonance spectroscopy. Endurance performance was evaluated according to the total work during dynamic handgrip exercise at 30% MVC at 1 Hz until exhaustion. Muscle oxidative capacity and total work deterioration was restricted to the IMM (P < 0.05) group. MVC decreased in the IMM and IMM + EST1 (P < 0.05) groups. However, the MVC amplitude decrease in the IMM + EST1 group was smaller than that in the IMM (P < 0.05) group. MVC remained unchanged in the other groups. During the 3-week immobilization, twice-weekly low-volume muscle endurance and strength training prevented deterioration in muscle strength, oxidative capacity, and endurance performance. Moreover, once-weekly muscle endurance and strength training prevented the deterioration of muscle oxidative capacity and endurance performance, and attenuated the degree of muscle strength decline.