Effects of a 10-Week Exercise and Nutritional Intervention with Variable Dietary Carbohydrates and Glycaemic Indices on Substrate Metabolism, Glycogen Storage, and Endurance Performance in Men: A Randomized Controlled Trial.

BACKGROUND: Daily nutrition plays an important role in supporting training adaptions and endurance performance. The objective of this 10-week study was to investigate the consequences of varying carbohydrate consumption and the glycaemic index (GI) together with an endurance training regimen on substrate oxidation, muscle energy storage and endurance performance under free-living conditions. Sixty-five moderately trained healthy men (29 ± 4 years; VO2 peak 55 ± 8 mL min-1 kg-1) were randomized to one of three different nutritional regimes (LOW-GI: 50-60% CHO with ≥ 65% of these CHO with GI < 50 per day, n = 24; HIGH-GI: 50-60% CHO with ≥ 65% CHO with GI > 70 per day, n = 20; LCHF: ≤ 50 g CHO daily, n = 21). Metabolic alterations and performance were assessed at baseline (T0) and after 10 weeks (T10) during a graded exercise treadmill test. Additionally, a 5 km time trial on a 400-m outdoor track was performed and muscle glycogen was measured by magnet resonance spectroscopy. RESULTS: Total fat oxidation expressed as area under the curve (AUC) during the graded exercise test increased in LCHF (1.3 ± 2.4 g min-1 × km h-1, p < 0.001), remained unchanged in LOW-GI (p > 0.05) and decreased in HIGH-GI (- 1.7 ± 1.5 g min-1 × km h-1, p < 0.001). After the intervention, LOW-GI (- 0.4 ± 0.5 mmol L-1 × km h-1, p < 0.001) and LCHF (- 0.8 ± 0.7 mmol L-1 × km h-1, p < 0.001) showed significantly lower AUC of blood lactate concentrations. Peak running speed increased in LOW-GI (T0: 4.3 ± 0.4 vs. T10: 4.5 ± 0.3 m s-1, p < 0.001) and HIGH-GI (T0: 4.4 ± 0.5 vs. T10: 4.6 ± 0.4 m s-1), while no improvement was observed in LCHF. Yet, time trial performance improved significantly in all groups. Muscle glycogen content increased for participants in HIGH-GI (T0: 97.3 ± 18.5 vs. T10: 144.5 ± 39.8 mmol L wet-tissue-1, p = 0.027) and remained unchanged in the LOW-GI and the LCHF group. At the last examination, muscle glycogen concentration was significantly higher in LOW-GI compared to LCHF (p = 0.014). CONCLUSION: Changes in fat oxidation were only present in LCHF, however, lower lactate concentrations in LOW-GI resulted in changes indicating an improved substrate metabolism. Compared to a LCHF diet, changes in peak running speed, and muscle glycogen stores were superior in LOW- and HIGH-GI diets. The low GI diet seems to have an influence on substrate metabolism without compromising performance at higher intensities, suggesting that a high-carbohydrate diet with a low GI is a viable alternative to a LCHF or a high GI diet. TRIAL REGISTRATION: Clinical Trials, NCT05241730. https://clinicaltrials.gov/study/NCT05241730 . Registered 25 January 2021.

Correlation between skeletal muscle acetylcarnitine and phosphocreatine metabolism during submaximal exercise and recovery: interleaved 1H/31P MRS 7 T study.

Acetylcarnitine is an essential metabolite for maintaining metabolic flexibility and glucose homeostasis. The in vivo behavior of muscle acetylcarnitine content during exercise has not been shown with magnetic resonance spectroscopy. Therefore, this study aimed to explore the behavior of skeletal muscle acetylcarnitine during rest, plantar flexion exercise, and recovery in the human gastrocnemius muscle under aerobic conditions. Ten lean volunteers and nine overweight volunteers participated in the study. A 7 T whole-body MR system with a double-tuned surface coil was used to acquire spectra from the gastrocnemius medialis. An MR-compatible ergometer was used for the plantar flexion exercise. Semi-LASER-localized 1H MR spectra and slab-localized 31P MR spectra were acquired simultaneously in one interleaved exercise/recovery session. The time-resolved interleaved 1H/31P MRS acquisition yielded excellent data quality. A between-group difference in acetylcarnitine metabolism over time was detected. Significantly slower τPCr recovery, τPCr on-kinetics, and lower Qmax in the overweight group, compared to the lean group was found. Linear relations between τPCr on-kinetics, τPCr recovery, VO2max and acetylcarnitine content were identified. In conclusion, we are the first to show in vivo changes of skeletal muscle acetylcarnitine during acute exercise and immediate exercise recovery with a submaximal aerobic workload using interleaved 1H/31P MRS at 7 T.

Gpcpd1-GPC metabolic pathway is dysfunctional in aging and its deficiency severely perturbs glucose metabolism.

Skeletal muscle plays a central role in the regulation of systemic metabolism during lifespan. With aging, this function is perturbed, initiating multiple chronic diseases. Our knowledge of mechanisms responsible for this decline is limited. Glycerophosphocholine phosphodiesterase 1 (Gpcpd1) is a highly abundant muscle enzyme that hydrolyzes glycerophosphocholine (GPC). The physiological functions of Gpcpd1 remain largely unknown. Here we show, in mice, that the Gpcpd1-GPC metabolic pathway is perturbed in aged muscles. Further, muscle-specific, but not liver- or fat-specific, inactivation of Gpcpd1 resulted in severely impaired glucose metabolism. Western-type diets markedly worsened this condition. Mechanistically, Gpcpd1 muscle deficiency resulted in accumulation of GPC, causing an 'aged-like' transcriptomic signature and impaired insulin signaling in young Gpcpd1-deficient muscles. Finally, we report that the muscle GPC levels are markedly altered in both aged humans and patients with type 2 diabetes, displaying a high positive correlation between GPC levels and chronological age. Our findings reveal that the muscle GPCPD1-GPC metabolic pathway has an important role in the regulation of glucose homeostasis and that it is impaired during aging, which may contribute to glucose intolerance in aging.

Effects of gender-affirming hormone therapy on cardiovascular risk factors focusing on glucose metabolism in an Austrian transgender cohort.

Objective: We aimed to investigate the effect of gender-affirming hormone therapy (GAHT) on cardiovascular disease risk factors focusing on glucose tolerance. Patients and Methods: This primarily translational study enrolled 16 transgender persons assigned female at birth (AFAB), 22 assigned male at birth (AMAB), and 33 age- and BMI-matched cisgender controls at the Medical University of Vienna from 2013 to 2020. A 3-Tesla MRI scan to measure intramyocardial, pancreatic, hepatic fat content and subcutaneous-to-visceral adipose tissue ratio (SAT/VAT-ratio), an oral glucose tolerance test (oGTT), bloodwork including brain natriuretic peptide (pro-BNP), sex hormones and two glucose-metabolism related biomarkers (adiponectin, betatrophin) were performed. Results: Estrogen intake was associated with higher fasting insulin (p = 0.034) and Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) (p = 0.037), however, lower HbA1c levels (p = 0.031) in AMAB than cisgender males. Adiponectin (p = 0.001) and betatrophin (p = 0.034) levels were higher in AMAB than cisgender males, but similar to cisgender females. Compared to cisgender females, AFAB displayed no differences in glucose metabolism or SAT/VAT-ratio. AFAB had lower pro-BNP levels (p = 0.014), higher liver enzymes (AST: p = 0.011; ALT: p = 0.012) and lower HDL levels (p = 0.017) than cisgender females, but comparable levels to cisgender males. AMAB showed an increased heart rate (p < 0.001) and pro-BNP (p = 0.002) levels, but a more favorable SAT/VAT-ratio (p = 0.013) and lower creatine kinase (CK) (p = 0.001) than cisgender males. There were no relevant differences in organ fat content between transgender persons and their respective cisgender controls. Conclusion: In AMAB, most investigated parameters adapted to levels seen in cisgender females except for parameters related to fasted insulin resistance. AMAB should be monitored with respect to the development of insulin resistance.

Combined exenatide and dapagliflozin has no additive effects on reduction of hepatocellular lipids despite better glycaemic control in patients with type 2 diabetes mellitus treated with metformin: EXENDA, a 24-week, prospective, randomized, placebo-controlled pilot trial.

AIMS: To investigate the potential synergistic effects of combined exenatide (EXE) and dapagliflozin (DAPA) versus (PLAC) placebo and DAPA on hepatocellular lipid (HCL) reduction after 24 weeks of treatment. MATERIALS AND METHODS: Thirty patients with type 2 diabetes were randomized to weekly EXE and daily DAPA (n = 16) or weekly PLAC and daily DAPA (n = 14). Inclusion criteria were glycated haemoglobin (HbA1c) 48 to 97 mmol/mol (6.5-11%), age 18 to 75 years, body mass index (BMI) ≥25 kg/m2 and metformin ≥1000 mg. The primary endpoint, HCL levels, were measured at baseline and after 24 weeks of treatment using magnetic resonance spectroscopy. Between-group effects were analysed using general linear models, adjusted for baseline outcome variables, age, sex and BMI. Within-group differences were assessed using a paired t-test. RESULTS: After 24 weeks, HCLs were reduced in both treatment groups (absolute change from baseline: EXE + DAPA -4.4%, 95% confidence interval [CI] -8.2, -0.7, P < 0.05; PLAC + DAPA -3.9%, 95% CI -6.0, -1.7, P < 0.01; relative change: EXE + DAPA -35.6%, PLAC + DAPA -32.3%) with no difference between groups. Similar findings were observed for subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT). HbA1c (EXE + DAPA -17.8 mmol/mol, [95% CI -24.8, -10.8], P <0.001; PLAC + DAPA -6.9 mmol/mol, [95% CI -10.5, -3.3], P = 0.001) and fasting glucose significantly decreased in both groups, although EXE + DAPA achieved better glycaemic control than PLAC + DAPA (adjusted difference: HbA1c -6.0 mmol/mol [95% CI -9.7, -2.2], P < 0.01). Body weight was reduced in both treatment groups (EXE + DAPA -7.3 kg, 95% CI -9.9, -4.8, P <0.001; PLAC + DAPA -4.6 kg, 95% CI -7.4, -1.8, P <0.01) with comparable results between groups. Changes in HCLs and weight, hip and waist circumference, VAT and SAT were positively associated. CONCLUSION: After 24 weeks, HCLs were significantly but comparably reduced in the EXE + DAPA and PLAC + DAPA groups, despite significantly better glycaemic control in the combined group EXE + DAPA. Changes in HCLs were associated with weight loss and reduction of visceral adiposity, but not with glucose control. Further studies are necessary to evaluate possible additional long-term effects of a combined treatment.

In Vivo 1 H MR Spectroscopy of Biliary Components of Human Gallbladder at 7T.

BACKGROUND: Previous in vivo proton MR spectroscopy (MRS) studies have demonstrated the possibility of quantifying amide groups of conjugated bile acids (NHCBA), olefinic lipids and cholesterol (OLC), choline-containing phospholipids (CCPLs), taurine and glycine conjugated bile acids (TCBA, GCBA), methylene group of lipids (ML), and methyl groups of bile acids, lipids, and cholesterol (BALC1.0, BALC0.9, and TBAC) in the gallbladder, which may be useful for the study of cholestatic diseases and cholangiopathies. However, these studies were performed at 1.5T and 3T, and higher magnetic fields may offer improved spectral resolution and signal intensity. PURPOSE: To develop a method for gallbladder MRS at 7T. STUDY TYPE: Retrospective, technical development. POPULATION: Ten healthy subjects (five males and five females), two patients with primary biliary cholangitis (PBC) (one male and one female), and one patient with primary sclerosing cholangitis (PSC) (female). FIELD STRENGTH/SEQUENCE: Free-breathing single-voxel MRS with a modified stimulated echo acquisition mode (STEAM) sequence at 7T. ASSESSMENT: Postprocessing was based on the T2 relaxation of water in the gallbladder and in the liver. Concentrations of biliary components were calculated using water signal. All data were corrected for T2 relaxation times measured in healthy subjects. STATISTICAL TESTS: The range of T2 relaxation time and concentration per bile component, and the resulting mean and standard deviation, were calculated. RESULTS: The concentrations of gallbladder components in healthy subjects were: NHCBA: 93 ± 66 mM, OLC: 154 ± 124 mM, CCPL: 42 ± 17 mM, TCBA: 48 ± 35 mM, GCBA: 67 ± 32 mM, ML: 740 ± 391 mM, BALC1.0: 175 ± 92 mM, BALC0.9: 260 ± 138 mM, and TBAC: 153 ± 90 mM. Mean concentrations of all bile components were found to be lower in patients. DATA CONCLUSION: This work provides a protocol for designing future MRS investigations of the bile system in vivo. EVIDENCE LEVEL: 2 TECHNICAL EFFICACY STAGE: 1.

Muscle-Specific Relation of Acetylcarnitine and Intramyocellular Lipids to Chronic Hyperglycemia: A Pilot 3-T 1H MRS Study.

OBJECTIVE: Acetylcarnitine plays an important role in fat metabolism and can be detected in proton magnetic resonance spectra in skeletal muscle. An inverse relationship of acetylcarnitine to intramyocellular lipids and metabolic markers of chronic hyperglycemia has been suggested. This study aimed to compare the acetylcarnitine concentrations and intramyocellular lipids measured noninvasively by proton magnetic resonance spectroscopy (1H MRS) in the tibialis anterior and the soleus of three different groups of volunteers with a broad range of glycemic control. METHODS: Acetylcarnitine and intramyocellular lipid concentrations were measured in 35 individuals stratified into three groups according to glucose tolerance and/or manifestation of type 2 diabetes mellitus. All MRS measurements were performed on a 3-T MR system. RESULTS: The differences in patient phenotype were mirrored by increased intramyocellular lipids in the tibialis anterior and decreased acetylcarnitine concentrations in the soleus muscle of type 2 diabetes patients when compared with normal glucose-tolerant individuals. Results suggest that intramyocellular lipids mirror whole-body glucose tolerance better in the tibialis anterior muscle, whereas acetylcarnitine is a better discriminator in the soleus muscle. CONCLUSIONS: This muscle-specific behavior of metabolites could represent different fiber compositions in the examined muscles and should be considered when planning future metabolic studies.

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 (τ PCr ) 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.

Decreased Compressional Sound Velocity Is an Indicator for Compromised Bone Stiffness in X-Linked Hypophosphatemic Rickets (XLH).

Objectives: To assess the diagnostic potential of bidirectional axial transmission (BDAT) ultrasound, and high-resolution peripheral quantitative computed tomography (HR-pQCT) in X-linked hypophosphatemia (XLH, OMIM #307800), a rare genetic disorder of phosphate metabolism caused by mutations in the PHEX gene. Methods: BDAT bone ultrasound was performed at the non-dominant distal radius (33% relative to distal head) and the central left tibia (50%) in eight XLH patients aged between 4.2 and 20.8 years and compared to twenty-nine healthy controls aged between 5.8 and 22.4 years. In eighteen controls, only radius measurements were performed. Four patients and four controls opted to participate in HR-pQCT scanning of the ultradistal radius and tibia. Results: Bone ultrasound was feasible in patients and controls as young as 4 years of age. The velocity of the first arriving signal (νFAS) in BDAT ultrasound was significantly lower in XLH patients compared to healthy controls: In the radius, mean νFAS of XLH patients and controls was 3599 ± 106 and 3866 ± 142 m/s, respectively (-6.9%; p < 0.001). In the tibia, it was 3578 ± 129 and 3762 ± 124 m/s, respectively (-4.9%; p = 0.006). HR-pQCT showed a higher trabecular thickness in the tibia of XLH patients (+16.7%; p = 0.021). Conclusions: Quantitative bone ultrasound revealed significant differences in cortical bone quality of young XLH patients as compared to controls. Regular monitoring of XLH patients by a radiation-free technology such as BDAT might provide valuable information on bone quality and contribute to the optimization of treatment. Further studies are needed to establish this affordable and time efficient method in the XLH patients.

Acute and regular exercise distinctly modulate serum, plasma and skeletal muscle BDNF in the elderly.

Brain-derived neurotrophic factor (BDNF) participates in orchestrating the adaptive response to exercise. However, the importance of transient changes in circulating BDNF for eliciting whole-body and skeletal muscle exercise benefits in humans remains relatively unexplored. Here, we investigated effects of acute aerobic exercise and 3-month aerobic-strength training on serum, plasma and skeletal muscle BDNF in twenty-two sedentary older individuals (69.0 ±â€¯8.0 yrs., 9 M/13F). BDNF response to acute exercise was additionally evaluated in young trained individuals (25.1 ±â€¯2.1 yrs., 3 M/5F). Acute aerobic exercise transiently increased serum BDNF in sedentary (16%, p = .007) but not in trained elderly or young individuals. Resting serum or plasma BDNF was not regulated by exercise training in the elderly. However, subtle training-related changes of serum BDNF positively correlated with improvements in walking speed (R = 0.59, p = .005), muscle mass (R = 0.43, p = .04) and cognitive performance (R = 0.41, p = .05) and negatively with changes in body fat (R = -0.43, p = .04) and triglyceridemia (R = -0.53, p = .01). Individuals who increased muscle BDNF protein in response to 3-month training (responders) displayed stronger acute exercise-induced increase in serum BDNF than non-responders (p = .006). In addition, muscle BDNF protein content positively correlated with type II-to-type I muscle fiber ratio (R = 0.587, p = .008) and with the rate of post-exercise muscle ATP re-synthesis (R = 0.703, p = .005). Contrary to serum, acute aerobic exercise resulted in a decline of plasma BDNF 1 h post-exercise in both elderly-trained (-34%, p = .002) and young-trained individuals (-48%, p = .034). Acute circulating BDNF regulation by exercise was dependent on the level of physical fitness and correlated with training-induced improvements in metabolic and cognitive functions. Our observations provide an indirect evidence that distinct exercise-induced changes in serum and plasma BDNF as well as training-related increase in muscle BDNF protein, paralleled by improvements in muscle and whole-body clinical phenotypes, are involved in the coordinated adaptive response to exercise in humans.

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.

Detection and Alterations of Acetylcarnitine in Human Skeletal Muscles by 1H MRS at 7 T.

OBJECTIVES: The aims of this study were to detect the acetylcarnitine resonance line at 2.13 ppm in the human vastus lateralis and soleus muscles, assess T1 and T2 relaxation times, and investigate the diurnal and exercise-related changes in absolute concentration noninvasively, using proton magnetic resonance spectroscopy at 7 T. MATERIALS AND METHODS: All measurements were performed on a 7 T whole-body Magnetom MR system with a 28-channel knee coil. Five healthy, moderately trained volunteers participated in the assessment of the detectability, repeatability, and relaxation times of acetylcarnitine. For the evaluation of the effect of training status, another 5 healthy, normally active volunteers were examined. In addition, normally active volunteers underwent a day-long protocol to estimate diurnal changes and response to the exercise. RESULTS: Using a long echo time of 350 milliseconds, we were able to detect the acetylcarnitine resonance line at 2.13 ppm in both muscle groups without significant lipid contamination. The T1 of acetylcarnitine in the vastus lateralis muscle was found to be 1807.2 ± 513.1 milliseconds and T2 was found to be 129.9 ± 44.9 milliseconds. Concentrations of acetylcarnitine from the vastus lateralis muscle in moderately trained volunteers were higher than concentrations from normally active volunteers. Acetylcarnitine concentrations changed during the day, tending to be higher in the morning after an overnight fast than after lunch. After 10 minutes of high-intensity exercise, the concentration significantly increased, and 15 minutes after cessation of exercise, a decrease could be observed. CONCLUSIONS: Our results demonstrate an effective detection of acetylcarnitine using a long TE of 350 milliseconds at 7 T in the vastus lateralis and soleus muscles with high repeatability and reliability on a 7 T scanner. Our data emphasize the need for strict standardization, physical activity, and dietary conditions for the measurement of the acetylcarnitine.

Aerobic-Strength Exercise Improves Metabolism and Clinical State in Parkinson's Disease Patients.

Regular exercise ameliorates motor symptoms in Parkinson's disease (PD). Here, we aimed to provide evidence that exercise brings additional benefits to the whole-body metabolism and skeletal muscle molecular and functional characteristics, which might help to explain exercise-induced improvements in the clinical state. 3-months supervised endurance/strength training was performed in early/mid-stage PD patients and age/gender-matched individuals (n = 11/11). The effects of exercise on resting energy expenditure (REE), glucose metabolism, adiposity, and muscle energy metabolism (31P-MRS) were evaluated and compared to non-exercising PD patients. Two muscle biopsies were taken to determine intervention-induced changes in fiber type, mitochondrial content, and expression of genes related to muscle energy metabolism, as well as proliferative and regenerative capacity. Exercise improved the clinical disability score (MDS-UPDRS), bradykinesia, balance, walking speed, REE, and glucose metabolism and increased muscle expression of energy sensors (AMPK). However, the exercise-induced increase in muscle mass/strength, mitochondrial content, type II fiber size, and postexercise phosphocreatine (PCr) recovery (31P-MRS) were found only in controls. Nevertheless, MDS-UPDRS was associated with muscle AMPK and mechano-growth factor (MGF) expression. Improvements in fasting glycemia were positively associated with muscle function and the expression of Sirt1 and Cox7a1, and the parameters of fitness/strength were positively associated with the expression of MyHC2, MyHC7, and MGF. Moreover, reduced bradykinesia was associated with better muscle metabolism (maximal oxidative capacity and postexercise PCr recovery; 31P-MRS). Exercise training improved the clinical state in early/mid-stage Parkinson's disease patients, including motor functions and whole-body metabolism. Although the adaptive response to exercise in PD was different from that of controls, exercise-induced improvements in the PD clinical state were associated with specific adaptive changes in muscle functional, metabolic, and molecular characteristics. CLINICAL TRIAL REGISTRATION: www.ClinicalTrials.gov, identifier NCT02253732.