Phosphocreatine Recovery Rate Research Articles

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...

Exploring the links of skeletal muscle mitochondrial oxidative capacity, physical functionality, and mental well-being of cancer survivors

Physical impairments following cancer treatment have been linked with the toxic effects of these treatments on muscle mass and strength, through their deleterious effects on skeletal muscle mitochondrial oxidative capacity. Accordingly, we designed the present study to explore relationships of skeletal muscle mitochondrial oxidative capacity with physical performance and perceived cancer-related psychosocial experiences of cancer survivors. We assessed skeletal muscle mitochondrial oxidative capacity using in vivo phosphorus-31 magnetic resonance spectroscopy (31P MRS), measuring the postexercise phosphocreatine resynthesis time constant, τPCr, in 11 post-chemotherapy participants aged 34–70 years. During the MRS procedure, participants performed rapid ballistic knee extension exercise to deplete phosphocreatine (PCr); hence, measuring the primary study outcome, which was the recovery rate of PCr (τPCr). Patient-reported outcomes of psychosocial symptoms and well-being were assessed using the Patient-Reported Outcomes Measurement Information System and the 36-Item Short Form health survey (SF-36). Rapid bioenergetic recovery, reflected through a smaller value of τPCr was associated with worse depression (rho ρ = − 0.69, p = 0.018, and Cohen’s d = − 1.104), anxiety (ρ = − 0.61, p = .046, d = − 0.677), and overall mental health (ρ = 0.74, p = 0.010, d = 2.198) scores, but better resilience (ρ = 0.65, p = 0.029), and coping-self efficacy (ρ = 0.63, p = 0.04) scores. This is the first study to link skeletal muscle mitochondrial oxidative capacity with subjective reports of cancer-related behavioral toxicities. Further investigations are warranted to confirm these findings probing into the role of disease status and personal attributes in these preliminary results.

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.

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.

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.

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.

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.

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.

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...

Impaired Skeletal Muscle Mitochondrial Efficiency in Smokers

Introduction Cigarette smoke can directly contribute to the development of skeletal muscle dysfunction. Mitochondrial oxidative capacity, a product of energy production efficiency and oxygen consumption, is important for skeletal muscle health. Whether mitochondrial energy production efficiency and muscle oxygen consumption play a role into skeletal muscle dysfunction in smokers has yet to be investigated. Thus, this study sought to test the hypothesis that mitochondrial oxidative capacity and mitochondrial efficiency are reduced in smokers compared to non-smokers. Methods 30 active smokers (Age: 33 ± 4 yrs, BMI: 30.8 ± 11.7 kg/m2) and 30 demographically matched healthy controls (Age: 33 ± 3 yrs, BMI: 32.5 ± 9.1 kg/m2) participated in this study. Participants self-reported the number of cigarettes smoked per day in the past 30 days. Near infrared spectroscopy (NIRS) was used to assess changes in oxygenated (O2Hb) and deoxygenated (HHb) hemoglobin/myoglobin of the gastrocnemius following 15s of electrical stimulation and multiple rapid arterial occlusions. The phosphocreatine (PCr) recovery rate constant (kPCr), an index of mitochondrial oxidative capacity, was calculated by fitting post-stimulation measurements to a monoexponential curve. Muscle oxygen consumption (mVO2 = abs[([ΔO2Hb – Δ HHb]/2] × 60)/(10 × 1.04) x4] × 22.4/1000) was calculated for each occlusion and the slopes of the total hemoglobin (tHb = O2Hb+HHb) signal following each occlusion were converted to muscle blood flow [mBF = 1/hemoglobin (mmol/L) × ΔtHb/Δtime]. Mitochondrial efficiency (MEFF) was calculated by the dividing the estimated mVO2 needed to achieve kPcr at 100% (mVO2estimated) efficiency by the observed mVO2 [Meff = (mVO2estimated/mVO2observed) × 100]. Results The average cigarettes smoked was 5 ± 3 cigarettes per day. kPcr was significantly (p = 0.022) reduced in smokers (1.99 ± 0.19 min-1) compared to non-smokers (2.54 ± 0.19 min-1). Compared to non-smokers (157.2 ± 45.5%), MEFF was significantly (p = 0.025) attenuated in smokers (46.5 ± 10.1%) and significantly associated with mVO2 (r = -0.409, p = 0.009) and kPcr (r = 0.461, p =0.003). Average mVO2 (p = 0.231) and mBF (p = 0.993)were not significantly different in smokers compared to non-smokers. Conclusion Muscle mitochondrial oxidative capacity and mitochondrial efficiency are reduced in smokers compared to non-smokers. However, skeletal muscle blood flow and oxygen consumption were not different between groups. Taken together, mitochondrial oxidative capacity may be reduced prior to alterations in blood flow and oxygen consumption or delivery in young smokers.

The impact of statin therapy and aerobic exercise training on skeletal muscle and whole-body aerobic capacity

BackgroundStatin use is widely recognized for improving cardiovascular health, but questions remain on how statin use influences skeletal muscle, particularly mitochondrial function. Study objective, design and participantsThe influence of statin therapy and exercise (EX) on aerobic capacity was determined. In Study1, skeletal muscle aerobic capacity was measured before and after 80 mg atorvastatin therapy. In Study2, aerobic capacity (skeletal muscle and whole body) was measured before and after a 12-week exercise randomized control trial in older adults (age = 67 ± 5 yrs.), a subset of which were on chronic low-moderate intensity statin therapy. Main outcome measuresMuscle oxidative capacity was determined from the phosphocreatine recovery rate constant (kPCr) using 31P Magnetic Resonance Spectroscopy. Whole body peak oxygen uptake (VO2 peak) was measured during a graded exercise test with indirect calorimetry. ResultsHigh dose statin therapy resulted in a 12% reduction in muscle oxidative capacity (pre = 1.34 ± 0.34 min−1, post = 1.17 ± 0.25 min−1, p = 0.004). Similarly, chronic low-moderate dose statin therapy was associated with lower muscle oxidative capacity at baseline (1.50 ± 0.35 min−1) compared to non-statin users (1.88 ± 0.047 min−1, p = 0.019). Following EX, muscle oxidative capacity increased by 35–40% (statin: Pre: 1.39 ± 0.44 vs. Post: 1.88 ± 0.47 min−1, no statin Pre: 1.86 ± 0.58 vs. Post: 2.58 ± 0.85 min−1) compared to control groups (Pre: 1.74 ± 0.27 vs Post: 1.75 ± 0.49 min−1, p = 0.001). VO2 peak increased by 11% for EX groups (Pre: 18.8 ± 2.8 vs. Post: 20.8 ± 3.0 ml·kg−1·min−1) following training compared to a small decline in controls (Pre: 21.8 ± 3.7 vs. Post: 20.8 ± 3.04 ml·kg−1·min−1, p = 0.001). ConclusionsStatin therapy resulted in reduced muscle oxidative capacity. Aerobic exercise improved skeletal muscle oxidative capacity and whole-body aerobic capacity during statin therapy.

42 Is Mitochondrial Function Measured by 31P Magnetic Resonance Spectroscopy Associated with Physical Performance in Older People with Functional Impairment?

Abstract Background Mitochondrial dysfunction has been proposed as a therapeutic target to improve muscle strength and endurance, but the contribution that mitochondrial dysfunction makes to impaired skeletal muscle performance in older people remains unclear. We studied the relationship between phosphocreatine recovery rate (a measure of skeletal muscle mitochondrial function) and physical performance in older people. Methods We analysed data from the Allopurinol in Functional Impairment (ALFIE) trial. Participants aged 65 and over, who were unable to walk 400 m in six minutes, underwent 31P magnetic resonance spectroscopy of the calf after exercise at baseline and at 20 weeks follow up. The phosphocreatine recovery half-life time (t-half) was derived as a measure of mitochondrial function. Participants also undertook the 6-minute walk distance, the Short Physical Performance Battery test (SPPB), and had muscle mass measured using bio-impedance analysis. Bivariate correlations and multivariable regression analyses were conducted to determine associations between t-half and baseline factors. Results One hundred and seventeen people underwent baseline 31P magnetic resonance spectroscopy, mean age 80.4 years (SD 6.0); 56 (48%) were female. Mean 6-minute walk was 291 m (SD 80) and mean SPPB score was 8.4 (SD 1.9). T-half was significantly correlated with SPPB score (r = 0.22, p = 0.02) but not with 6-minute walk distance (r = 0.10, p = 0.29). In multivariable linear regression, muscle mass and weight, but not t-half, were independently associated with SPPB score and with 6-minute walk distance. The change in t-half between baseline and 20 weeks was not significantly associated with the change in SPPB (r = 0.03, p = 0.79) or with the change in 6-minute walk distance (r = −0.11, p = 0.28). Conclusion Muscle mass, but not phosphocreatine recovery time, was associated with Short Physical Performance Battery score and 6-minute walk distance in this cohort of older people with functional impairment.

Post-exercise intramuscular O2 supply is tightly coupled with a higher proximal-to-distal ATP synthesis rate in human tibialis anterior.

Key points The post‐exercise recovery of phosphocreatine, a measure of the oxidative capacity of muscles, as assessed by 31P MR spectroscopy, shows a striking increase from distal to proximal along the human tibialis anterior muscle.To investigate why this muscle exhibits a greater oxidative capacity proximally, we tested whether the spatial variation in phosphocreatine recovery rate is related to oxygen supply, muscle fibre type or type of exercise.We revealed that oxygen supply also increases from distal to proximal along the tibialis anterior, and that it strongly correlated with phosphocreatine recovery. Carnosine level, a surrogate measure for muscle fibre type was not different between proximal and distal, and type of exercise did not affect the gradient in phosphocreatine recovery rate.Taken together, the findings of this study suggest that the post‐exercise spatial gradients in oxygen supply and phosphocreatine recovery are driven by a higher intrinsic mitochondrial oxidative capacity proximally. Phosphorus magnetic resonance spectroscopy (31P MRS) of human tibialis anterior (TA) revealed a strong proximo‐distal gradient in the post‐exercise phosphocreatine (PCr) recovery rate constant (k PCr), a measure of muscle oxidative capacity. The aim of this study was to investigate whether this k PCr gradient is related to O2 supply, resting phosphorylation potential, muscle fibre type, or type of exercise. Fifteen male volunteers performed continuous isometric ankle dorsiflexion at 30% maximum force until exhaustion. At multiple locations along the TA, we measured the oxidative PCr resynthesis rate (V PCr = k PCr × PCr depletion) by 31P MRS, the oxyhaemoglobin recovery rate constant (k O2Hb) by near infrared spectroscopy, and muscle perfusion with MR intravoxel incoherent motion imaging. The k O2Hb, k PCr, V PCr and muscle perfusion depended on measurement location (P < 0.001, P < 0.001, P = 0.032 and P = 0.003, respectively), all being greater proximally. The k O2Hb and muscle perfusion correlated with k PCr (r = 0.956 and r = 0.852, respectively) and V PCr (r = 0.932 and r = 0.985, respectively), the latter reflecting metabolic O2 consumption. Resting phosphorylation potential (PCr/inorganic phosphate) was also higher proximally (P < 0.001). The surrogate for fibre type, carnosine content measured by 1H MRS, did not differ between distal and proximal TA (P = 0.884). Performing intermittent exercise to avoid exercise ischaemia, still led to larger k PCr proximally than distally (P = 0.013). In conclusion, the spatial k PCr gradient is strongly associated with the spatial variation in O2 supply. It cannot be explained by exercise‐induced ischaemia nor by fibre type. Our findings suggest it is driven by a higher proximal intrinsic mitochondrial oxidative capacity, apparently to support contractile performance of the TA.

Effect of allopurinol on phosphocreatine recovery and muscle function in older people with impaired physical function: a randomised controlled trial.

BackgroundAllopurinol has vascular antioxidant effects and participates in purinergic signalling within muscle. We tested whether allopurinol could improve skeletal muscle energetics and physical function in older people with impaired physical performance.MethodsWe conducted a randomised, double blind, parallel group, placebo-controlled trial, comparing 20 weeks of allopurinol 600 mg once daily versus placebo. We recruited community-dwelling participants aged 65 and over with baseline 6-min walk distance of <400 m and no contraindications to magnetic resonance imaging scanning. Outcomes were measured at baseline and 20 weeks. The primary outcome was post-exercise phosphocreatine (PCr) recovery rate measured using 31P magnetic resonance spectroscopy of the calf. Secondary outcomes included 6-min walk distance, short physical performance battery (SPPB), lean body mass measured by bioimpedance, endothelial function and quality of life.ResultsIn total, 124 participants were randomised, mean age 80 (SD 6) years. A total of 59 (48%) were female, baseline 6-min walk distance was 293 m (SD 80 m) and baseline SPPB was 8.5 (SD 2.0). Allopurinol did not significantly improve PCr recovery rate (treatment effect 0.10 units [95% CI, −0.07 to 0.27], P = 0.25). No significant changes were seen in endothelial function, quality of life, lean body mass or SPPB. Allopurinol improved 6-min walk distance (treatment effect 25 m [95% 4–46, P = 0.02]). This was more pronounced in those with high baseline oxidative stress and urate.ConclusionAllopurinol improved 6-min walk distance but not PCr recovery rate in older people with impaired physical function. Antioxidant strategies to improve muscle function for older people may need to be targeted at subgroups with high baseline oxidative stress.

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.)

Declining Skeletal Muscle Mitochondrial Function Associated With Increased Risk of Depression in Later Life

Late-life depression (LLD) is a chronic and heterogeneous disorder. Recent studies have implicated non-normative age-related processes in its pathogenesis. This investigation examined both cross-sectional and longitudinal associations between skeletal muscle mitochondrial function and LLD. Data from 603 men and women from the Baltimore Longitudinal Study on Aging were analyzed, of whom 167 provided data from a follow-up visit. Muscle bioenergetics was measured by postexercise recovery rate of phosphocreatine (PCr) using phosphorus magnetic resonance spectroscopy. Depressive symptoms were assessed using the Center for Epidemiologic Studies Depression (CES-D) Scale. There was no cross-sectional association between baseline depression status and either the PCr recovery rate constant (kPCr; t = -0.553, df = 542; p = 0.580) or mitochondrial capacity largely independent of exercise intensity (adenosine triphosphate maximum [ATPmax]; t = 0.804, df = 553; p = 0.422). Covariate-adjusted Firth logistic regression models however showed that greater decreases in skeletal muscle mitochondrial function from baseline to follow-up were associated with higher odds of clinically significant depressive symptoms (CES-D ≥16) at follow-up (ΔATPmax: odds ratio = 2.63, χ2 = 5.62, df =1; p = 0.018; ΔkPCr: odds ratio = 2.32, χ2 = 5.79, df =1; p = 0.016). Findings suggest that declining skeletal muscle mitochondrial function in older adults is associated with clinically significant depressive symptoms at follow-up, thereby providing preliminary support for the hypothesis that mitochondrial dysfunction may be a potential key pathophysiological mechanism in adults with LLD.

Exercise Response Variations in Skeletal Muscle PCr Recovery Rate and Insulin Sensitivity Relate to Muscle Epigenomic Profiles in Individuals With Type 2 Diabetes.

Some individuals with type 2 diabetes do not reap metabolic benefits from exercise training, yet the underlying mechanisms of training response variation are largely unexplored. We classified individuals with type 2 diabetes (n = 17) as nonresponders (n = 6) or responders (n = 11) based on changes in phosphocreatine (PCr) recovery rate after 10 weeks of aerobic training. We aimed to determine whether the training response variation in PCr recovery rate was marked by distinct epigenomic profiles in muscle prior to training. PCr recovery rate as an indicator of in vivo muscle mitochondrial function in vastus lateralis (31P-magnetic resonance spectroscopy), insulin sensitivity (M-value; hyperinsulinemic-euglycemic clamp), aerobic capacity (Vo2peak), and blood profiles were determined pretraining and post-training. Muscle biopsies were performed pretraining in vastus lateralis for the isolation of primary skeletal muscle cells (HSkMCs) and assessments of global DNA methylation and RNA sequencing in muscle tissue and HSkMCs. By design, nonresponders decreased and responders increased PCr recovery rate with training. In nonresponders, insulin sensitivity did not improve and glycemic control (HbA1c) worsened. In responders, insulin sensitivity improved. Vo2peak improved by ∼12% in both groups. Nonresponders and responders were distinguished by distinct pretraining molecular (DNA methylation, RNA expression) patterns in muscle tissue, as well as in HSkMCs. Enrichment analyses identified elevations in glutathione regulation, insulin signaling, and mitochondrial metabolism in nonresponders pretraining, which was reflected in vivo by higher pretraining PCr recovery rate and insulin sensitivity in these same individuals. A training response variation for clinical risk factors in individuals with type 2 diabetes is reflected by distinct basal myocellular epigenomic profiles in muscle tissue, some of which are maintained in HSkMCs, suggesting a cell-autonomous underpinning. Our data provide new evidence to potentially shift the diabetes treatment paradigm for individuals who do not benefit from training, such that supplemental treatment can be designed.

Oxidative capacity varies along the length of healthy human tibialis anterior.

During exercise skeletal muscles use the energy buffer phosphocreatine. The post-exercise recovery of phosphocreatine is a measure of the oxidative capacity of muscles and is traditionally assessed by 31 P magnetic resonance spectroscopy of a large tissue region, assuming homogeneous energy metabolism. To test this assumption, we collected spatially resolved spectra along the length of human tibialis anterior using a home-built array of 31 P detection coils, and observed a striking gradient in the recovery rate of phosphocreatine, decreasing along the proximo-distal axis of the muscle. A similar gradient along this muscle was observed in signal changes recorded by 1 H muscle functional MRI. These findings identify intra-muscular variation in the physiology of muscles in action and highlight the importance of localized sampling for any methodology investigating oxidative metabolism of this, and potentially other muscles. The rate of phosphocreatine (PCr) recovery (kPCr ) after exercise, characterizing muscle oxidative capacity, is traditionally assessed with unlocalized 31 P magnetic resonance spectroscopy (MRS) using a single surface coil. However, because of intramuscular variation in fibre type and oxygen supply, kPCr may be non-uniform within muscles. We tested this along the length of the tibialis anterior (TA) muscle in 10male volunteers. For this purpose, we employed a 3T MR system with a 31 P/1 H volume transmit coil combined with a home-built 31 P phased-array receive probe, consisting of five coil elements covering the TA muscle length. Mono-exponential kPCr was determined for all coil elements after 40s of submaximal isometric dorsiflexion (SUBMAX) and incremental exercise to exhaustion (EXH). In addition, muscle functional MRI (1 H mfMRI) was performed using the volume coil after another 40s of SUBMAX. A strong gradient in kPCr was observed along the TA (P<0.001), being two times higher proximally vs. distally during SUBMAX and EXH. Statistical analysis showed that this gradient cannot be explained by pH variations. A similar gradient was seen in the slope of the initial post-exercise 1 H mfMRI signal change, which was higher proximally than distally in both the TA and the extensor digitorum longus (P<0.001) and strongly correlated with kPCr . The pronounced differences along the TA in functional oxidative capacity identify regional variation in the physiological demand of this muscle during everyday activities and have implications for the bio-energetic assessment of interventions to modify its performance and of neuromuscular disorders involving the TA.