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Genetic therapy has changed the prognosis of hereditary proximal spinal muscular atrophy, although treatment efficacy has been variable. There is a clear need for deeper understanding of underlying causes of muscle weakness and exercise intolerance in patients with this disease to further optimize treatment strategies. Animal models suggest that in addition to motor neuron and associated musculature degeneration, intrinsic abnormalities of muscle itself including mitochondrial dysfunction contribute to the disease aetiology. To test this hypothesis in patients, we conducted the first in vivo clinical investigation of muscle bioenergetics. We recruited 15 patients and 15 healthy age and gender-matched control subjects in this cross-sectional clinico-radiological study. MRI and 31P magnetic resonance spectroscopy, the modality of choice to interrogate muscle energetics and phenotypic fibre-type makeup, was performed of the proximal arm musculature in combination with fatiguing arm-cycling exercise and blood lactate testing. We derived bioenergetic parameter estimates including: blood lactate, intramuscular pH and inorganic phosphate accumulation during exercise, and muscle dynamic recovery constants. A linear correlation was used to test for associations between muscle morphological and bioenergetic parameters and clinico-functional measures of muscle weakness. MRI showed significant atrophy of triceps but not biceps muscles in patients. Maximal voluntary contraction force normalized to muscle cross-sectional area for both arm muscles was 1.4-fold lower in patients than in controls, indicating altered intrinsic muscle properties other than atrophy contributed to muscle weakness in this cohort. In vivo31P magnetic resonance spectroscopy identified white-to-red remodelling of residual proximal arm musculature in patients on the basis of altered intramuscular inorganic phosphate accumulation during arm-cycling in red versus white and intermediate myofibres. Blood lactate rise during arm-cycling was blunted in patients and correlated with muscle weakness and phenotypic muscle makeup. Post-exercise metabolic recovery was slower in residual intramuscular white myofibres in patients demonstrating mitochondrial ATP synthetic dysfunction in this particular fibre type. This study provides the first in vivo evidence in patients that degeneration of motor neurons and associated musculature causing atrophy and muscle weakness in 5q spinal muscular atrophy type 3 and 4 is aggravated by disproportionate depletion of myofibres that contract fastest and strongest. Our finding of decreased mitochondrial ATP synthetic function selectively in residual white myofibres provides both a possible clue to understanding the apparent vulnerability of this particular fibre type in 5q spinal muscular atrophy types 3 and 4 as well as a new biomarker and target for therapy. [ABSTRACT FROM AUTHOR]

Glycogen storage disease type IIIa (GSDIIIa) is an inborn error of carbohydrate metabolism caused by a debranching enzyme deficiency. A subgroup of GSDIIIa patients develops severe myopathy. The purpose of this study was to investigate whether acute nutritional ketosis (ANK) in response to ketone‐ester (KE) ingestion is effective to deliver oxidative substrate to exercising muscle in GSDIIIa patients. This was an investigator‐initiated, researcher‐blinded, randomized, crossover study in six adult GSDIIIa patients. Prior to exercise subjects ingested a carbohydrate drink (~66 g, CHO) or a ketone‐ester (395 mg/kg, KE) + carbohydrate drink (30 g, KE + CHO). Subjects performed 15‐minute cycling exercise on an upright ergometer followed by 10‐minute supine cycling in a magnetic resonance (MR) scanner at two submaximal workloads (30% and 60% of individual maximum, respectively). Blood metabolites, indirect calorimetry data, and in vivo 31P‐MR spectra from quadriceps muscle were collected during exercise. KE + CHO induced ANK in all six subjects with median peak βHB concentration of 2.6 mmol/L (range: 1.6‐3.1). Subjects remained normoglycemic in both study arms, but delta glucose concentration was 2‐fold lower in the KE + CHO arm. The respiratory exchange ratio did not increase in the KE + CHO arm when workload was doubled in subjects with overt myopathy. In vivo 31P MR spectra showed a favorable change in quadriceps energetic state during exercise in the KE + CHO arm compared to CHO in subjects with overt myopathy. Effects of ANK during exercise are phenotype‐specific in adult GSDIIIa patients. ANK presents a promising therapy in GSDIIIa patients with a severe myopathic phenotype. Trial registration number: ClinicalTrials.gov identifier: NCT03011203. [ABSTRACT FROM AUTHOR]

Aim: Loss of skeletal muscle mass is a common clinical finding in cancer patients. The purpose of this meta‐analysis and systematic review was to quantify the effect of doxorubicin on skeletal muscle and report on the proposed molecular pathways possibly leading to doxorubicin‐induced muscle atrophy in both human and animal models. Methods: A systematic search of the literature was conducted in PubMed, EMBASE, Web of Science and CENTRAL databases. The internal validity of included studies was assessed using SYRCLE's risk of bias tool. Results: Twenty eligible articles were identified. No human studies were identified as being eligible for inclusion. Doxorubicin significantly reduced skeletal muscle weight (ie EDL, TA, gastrocnemius and soleus) by 14% (95% CI: 9.9; 19.3) and muscle fibre cross‐sectional area by 17% (95% CI: 9.0; 26.0) when compared to vehicle controls. Parallel to negative changes in muscle mass, muscle strength was even more decreased in response to doxorubicin administration. This review suggests that mitochondrial dysfunction plays a central role in doxorubicin‐induced skeletal muscle atrophy. The increased production of ROS plays a key role within this process. Furthermore, doxorubicin activated all major proteolytic systems (ie calpains, the ubiquitin‐proteasome pathway and autophagy) in the skeletal muscle. Although each of these proteolytic pathways contributes to doxorubicin‐induced muscle atrophy, the activation of the ubiquitin‐proteasome pathway is hypothesized to play a key role. Finally, a limited number of studies found that doxorubicin decreases protein synthesis by a disruption in the insulin signalling pathway. Conclusion: The results of the meta‐analysis show that doxorubicin induces skeletal muscle atrophy in preclinical models. This effect may be explained by various interacting molecular pathways. Results from preclinical studies provide a robust setting to investigate a possible dose‐response, separate the effects of doxorubicin from tumour‐induced atrophy and to examine underlying molecular pathways. More research is needed to confirm the proposed signalling pathways in humans, paving the way for potential therapeutic approaches. [ABSTRACT FROM AUTHOR]

Phosphorus-31 magnetic resonance spectroscopy (31P-MRS) is a unique non-invasive imaging modality for probing in vivo high-energy phosphate metabolism in the human heart. We investigated whether current 31P-MRS methodology would allow for clinical applications to detect exercise-induced changes in (patho-)physiological myocardial energy metabolism. Hereto, measurement variability and repeatability of three commonly used localized 31P-MRS methods [3D image-selected in vivo spectroscopy (ISIS) and 1D ISIS with 1D chemical shift imaging (CSI) oriented either perpendicular or parallel to the surface coil] to quantify the myocardial phosphocreatine (PCr) to adenosine triphosphate (ATP) ratio in healthy humans (n = 8) at rest were determined on a clinical 3 Tesla MR system. Numerical simulations of myocardial energy homeostasis in response to increased cardiac work rates were performed using a biophysical model of myocardial oxidative metabolism. Hypertrophic cardiomyopathy was modeled by either inefficient sarcomere ATP utilization or decreased mitochondrial ATP synthesis. The effect of creatine depletion on myocardial energy homeostasis was explored for both conditions. The mean in vivo myocardial PCr/ATP ratio measured with 3D ISIS was 1.57 ± 0.17 with a large repeatability coefficient of 40.4%. For 1D CSI in a 1D ISIS-selected slice perpendicular to the surface coil, the PCr/ATP ratio was 2.78 ± 0.50 (repeatability 42.5%). With 1D CSI in a 1D ISIS-selected slice parallel to the surface coil, the PCr/ATP ratio was 1.70 ± 0.56 (repeatability 43.7%). The model predicted a PCr/ATP ratio reduction of only 10% at the maximal cardiac work rate in normal myocardium. Hypertrophic cardiomyopathy led to lower PCr/ATP ratios for high cardiac work rates, which was exacerbated by creatine depletion. Simulations illustrated that when conducting cardiac 31P-MRS exercise stress testing with large measurement error margins, results obtained under pathophysiologic conditions may still lie well within the 95% confidence interval of normal myocardial PCr/ATP dynamics. Current measurement precision of localized 31P-MRS for quantification of the myocardial PCr/ATP ratio precludes the detection of the changes predicted by computational modeling. This hampers clinical employment of 31P-MRS for diagnostic testing and risk stratification, and warrants developments in cardiac 31P-MRS exercise stress testing methodology. [ABSTRACT FROM AUTHOR]

Data from 31P-nuclear magnetic resonance spectroscopy of human forearm flexor muscle were analyzed based on a previously developed model of mitochondrial oxidative phosphorylation (PLoS Comp Bio 1: e36, 2005) to test the hypothesis that substrate level (concentrations of ADP and inorganic phosphate) represents the primary signal governing the rate of mitochondrial ATP synthesis and maintaining the cellular ATP hydrolysis potential in skeletal muscle. Model-based predictions of cytoplasmic concentrations of phosphate metabolites (ATP, ADP, and Pi) matched data obtained from 20 healthy volunteers and indicated that as work rate is varied from rest to submaximal exercise commensurate increases in the rate of mitochondrial ATP synthesis are effected by changes in concentrations of available ADP and Pi. Additional data from patients with a defect of complex I of the respiratory chain and a patient with a deficiency in the mitochondrial adenine nucleotide translocase were also predicted the by the model by making the appropriate adjustments to the activities of the affected proteins associates with the defects, providing both further validation of the biophysical model of the control of oxidative phosphorylation and insight into the impact of these diseases on the ability of the cell to maintain its energetic state. [ABSTRACT FROM AUTHOR]

This review gives an overview of methods and outcomes of studies that compared circulatory, ventilatory, energetic or hormonal responses evoked by single-leg cycling and double-leg cycling at sub-maximal and maximal intensities. Through a systematic search, 18 studies were identified in the databases PubMed, Embase and Web of Science. Additionally, one study was added after a check of references. Critical analysis of each study showed that their quality was low to moderate. Between studies, widely divergent study procedures were present, such as different intensities, incremental or constant workloads, and different cycling frequencies. Moreover, a large variety of outcome variables was found and thereby comparison was hard. Nevertheless, results showed a tendency to higher hormonal levels of catecholamines as well as circulatory and ventilatory responses during double-leg cycling compared to one-leg cycling. Additionally, at similar normalized submaximal workloads, blood lactate levels tended to be lower during double-leg cycling, suggesting that more type II muscle fibers were recruited. From the reviewed studies the tentative conclusion is that active muscle mass seems a crucial factor in the regulation of endurance performance. Consequently, exercise regimens that recruit a larger active muscle mass, for example combined arm and leg exercise, would optimally stress the release of biochemicals and hence the modulation of central training adaptations, which may positively affect physical capacity in, for example, persons that have diminished leg muscle mass available. However, it also became clear that more information is needed to further understand the contributions of active muscle mass. The experimental possibilities of comparing one-legged and two-legged cycling is promising, but future studies should aim to provide complete quantitative data on the muscle mass recruited, as well as on the specific contribution of anaerobic/aerobic metabolism. They should also aim to include blood parameters such as PCO2, pH, myokines and physiological responses such as heart rate and ventilation. [ABSTRACT FROM AUTHOR]

The assessment of mitochondrial properties in skeletal muscle is important in clinical research, for instance in the study of diabetes. The gold standard to measure mitochondrial capacity non-invasively is the phosphocreatine (PCr) recovery rate after exercise, measured by 31P Magnetic Resonance spectroscopy (31P MRS). Here, we sought to expand the evidence base for an alternative method to assess mitochondrial properties which uses 31P MRS measurement of the Pi content of an alkaline compartment attributed to mitochondria (Pi2; as opposed to cytosolic Pi (Pi1)) in resting muscle at high magnetic field. Specifically, the PCr recovery rate in human quadriceps muscle was compared with the signal intensity of the Pi2 peak in subjects with varying mitochondrial content of the quadriceps muscle as a result of athletic training, and the results were entered into a mechanistic computational model of mitochondrial metabolism in muscle to test if the empirical relation between Pi2/Pi1 ratio and the PCr recovery was consistent with theory. Localized 31P spectra were obtained at 7T from resting vastus lateralis muscle to measure the intensity of the Pi2 peak. In the endurance trained athletes a Pi2/Pi1 ratio of 0.07 ± 0.01 was found, compared to a significantly lower (p<0.05) Pi2/Pi1 ratio of 0.03 ± 0.01 in the normally active group. Next, PCr recovery kinetics after in magnet bicycle exercise were measured at 1.5T. For the endurance trained athletes, a time constant τPCr 12 ± 3 s was found, compared to 24 ± 5s in normally active subjects. Without any parameter optimization the computational model prediction matched the experimental data well (r2 of 0.75). Taken together, these results suggest that the Pi2 resonance in resting human skeletal muscle observed at 7T provides a quantitative MR-based functional measure of mitochondrial density. [ABSTRACT FROM AUTHOR]