phosphocreatine and Mitochondrial-Diseases

Mutations in nuclear and mitochondrial DNA impacting mitochondrial function result in disease manifestations ranging from early death to abnormalities in all major organ systems and to symptoms that can be largely confined to muscle fatigue. The definitive diagnosis of a mitochondrial disorder can be difficult to establish. When the constellation of symptoms is suggestive of mitochondrial disease, neuroimaging features may be diagnostic and suggestive, can help direct further workup, and can help to further characterize the underlying brain abnormalities. Magnetic resonance imaging changes may be nonspecific, such as atrophy (both general and involving specific structures, such as cerebellum), more suggestive of particular disorders such as focal and often bilateral lesions confined to deep brain nuclei, or clearly characteristic of a given disorder such as stroke-like lesions that do not respect vascular boundaries in mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episode (MELAS). White matter hyperintensities with or without associated gray matter involvement may also be observed. Across patients and discrete disease subtypes (e.g., MELAS, Leigh syndrome, etc.), patterns of these features are helpful for diagnosis. However, it is also true that marked variability in expression occurs in all mitochondrial disease subtypes, illustrative of the complexity of the disease process. The present review summarizes the role of neuroimaging in the diagnosis and characterization of patients with suspected mitochondrial disease.

Topics: Adenosine Triphosphate; Aspartic Acid; Brain; Child; Developmental Disabilities; Diagnosis, Differential; Humans; Image Processing, Computer-Assisted; Lactic Acid; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Mitochondrial Diseases; Phosphocreatine

Substantial evidence indicates bioenergetic dysfunction and mitochondrial impairment contribute either directly and/or indirectly to the pathogenesis of numerous neurodegenerative disorders. Treatment paradigms aimed at ameliorating this cellular energy deficit and/or improving mitochondrial function in these neurodegenerative disorders may prove to be useful as a therapeutic intervention. Creatine is a molecule that is produced both endogenously, and acquired exogenously through diet, and is an extremely important molecule that participates in buffering intracellular energy stores. Once creatine is transported into cells, creatine kinase catalyzes the reversible transphosphorylation of creatine via ATP to enhance the phosphocreatine energy pool. Creatine kinase enzymes are located at strategic intracellular sites to couple areas of high energy expenditure to the efficient regeneration of ATP. Thus, the creatine kinase/phosphocreatine system plays an integral role in energy buffering and overall cellular bioenergetics. Originally, exogenous creatine supplementation was widely used only as an ergogenic aid to increase the phosphocreatine pool within muscle to bolster athletic performance. However, the potential therapeutic value of creatine supplementation has recently been investigated with respect to various neurodegenerative disorders that have been associated with bioenergetic deficits as playing a role in disease etiology and/or progression which include; Alzheimer's, Parkinson's, amyotrophic lateral sclerosis (ALS), and Huntington's disease. This review discusses the contribution of mitochondria and bioenergetics to the progression of these neurodegenerative diseases and investigates the potential neuroprotective value of creatine supplementation in each of these neurological diseases. In summary, current literature suggests that exogenous creatine supplementation is most efficacious as a treatment paradigm in Huntington's and Parkinson's disease but appears to be less effective for ALS and Alzheimer's disease.

Topics: Adenosine Triphosphate; Animals; Creatine; Dietary Supplements; Energy Metabolism; Humans; Mitochondria; Mitochondrial Diseases; Neurodegenerative Diseases; Phosphocreatine

Quantitative MRI and phosphorus magnetic resonance spectroscopy ((31)P-MRS) were used to investigate skeletal muscle metabolism in vivo in patients with dermatomyositis (DM) and polymyositis (PM) in order to evaluate the role of mitochondrial abnormalities in the pathogenesis and clinical expression of these conditions. Nine patients with DM (mean age +/- SD, 57 +/- 14 years) and five with PM (42 +/- 12 years) and with age at disease onset 53 +/- 16 and 38 +/- 12 years, respectively, were included in the study together with 18 age-matched controls. Post-exercise (31)P-MRS indices of muscle oxidative metabolism were all impaired in DM and PM. In both groups of patients, the phosphocreatine and adenosine diphosphate recovery half-times were almost twice as long as in controls (P < 0.05 for each variable) and the maximum rate of mitochondrial ATP production was half that found in normal subjects (P < 0.001). The rate of proton efflux from muscle fibres was significantly reduced in DM (P < 0.001) and PM (P = 0.02). The impairment of (31)P-MRS recovery indices in DM and PM patients was similar to that found in a group of 10 patients with a primary mitochondrial disorder that showed a normal proton efflux rate. There was no correlation between the MRS-detectable abnormalities and the degree of inflammation or fatty infiltration of the muscle, as measured by MRI. The in vivo findings in DM and PM patients indicate impaired muscle aerobic function, which, considering the reduced proton efflux, is likely to be secondary to an impaired blood supply. Our results suggest that the abnormal mitochondria seen in some muscle biopsies are unlikely to be the primary cause of the oxidative insufficiency in these patients.

Topics: Adenosine Diphosphate; Adenosine Triphosphate; Adult; Aged; Capillaries; Dermatomyositis; Exercise Test; Female; Humans; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Male; Middle Aged; Mitochondria; Mitochondrial Diseases; Muscle, Skeletal; Oxidative Phosphorylation; Phosphocreatine; Phosphorus Isotopes; Physical Exertion; Polymyositis; Protons; Reference Values; Rest; Water

Mitochondrial dysfunction is postulated to be central to amyotrophic lateral sclerosis (ALS) pathophysiology. Evidence comes primarily from disease models and conclusive data to support bioenergetic dysfunction in vivo in patients is currently lacking. This study is the first to assess mitochondrial dysfunction in brain and muscle in individuals living with ALS using 31P-magnetic resonance spectroscopy (MRS), the modality of choice to assess energy metabolism in vivo. We recruited 20 patients and 10 healthy age and gender-matched control subjects in this cross-sectional clinico-radiological study. 31P-MRS was acquired from cerebral motor regions and from tibialis anterior during rest and exercise. Bioenergetic parameter estimates were derived including: ATP, phosphocreatine, inorganic phosphate, adenosine diphosphate, Gibbs free energy of ATP hydrolysis (ΔGATP), phosphomonoesters, phosphodiesters, pH, free magnesium concentration, and muscle dynamic recovery constants. Linear regression was used to test for associations between brain data and clinical parameters (revised amyotrophic functional rating scale, slow vital capacity, and upper motor neuron score) and between muscle data and clinico-neurophysiological measures (motor unit number and size indices, force of contraction, and speed of walking). Evidence for primary dysfunction of mitochondrial oxidative phosphorylation was detected in the brainstem where ΔGATP and phosphocreatine were reduced. Alterations were also detected in skeletal muscle in patients where resting inorganic phosphate, pH, and phosphomonoesters were increased, whereas resting ΔGATP, magnesium, and dynamic phosphocreatine to inorganic phosphate recovery were decreased. Phosphocreatine in brainstem correlated with respiratory dysfunction and disability; in muscle, energy metabolites correlated with motor unit number index, muscle power, and speed of walking. This study provides in vivo evidence for bioenergetic dysfunction in ALS in brain and skeletal muscle, which appears clinically and electrophysiologically relevant. 31P-MRS represents a promising technique to assess the pathophysiology of mitochondrial function in vivo in ALS and a potential tool for future clinical trials targeting bioenergetic dysfunction.

Topics: Adenosine Triphosphate; Aged; Amyotrophic Lateral Sclerosis; Brain Chemistry; Cross-Sectional Studies; Energy Metabolism; Female; Humans; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Male; Middle Aged; Mitochondria; Mitochondrial Diseases; Motor Neurons; Muscle Contraction; Muscle Strength; Muscle, Skeletal; Oxidative Phosphorylation; Phosphocreatine; Walking

Rhabdomyolysis is common in very long-chain acyl-CoA dehydrogenase deficiency (VLCADD) and other metabolic myopathies, but its pathogenic basis is poorly understood. Here, we show that prolonged bicycling exercise against a standardized moderate workload in VLCADD patients is associated with threefold bigger changes in phosphocreatine (PCr) and inorganic phosphate (Pi) concentrations in quadriceps muscle and twofold lower changes in plasma acetyl-carnitine levels than in healthy subjects. This result is consistent with the hypothesis that muscle ATP homeostasis during exercise is compromised in VLCADD. However, the measured rates of PCr and Pi recovery post-exercise showed that the mitochondrial capacity for ATP synthesis in VLCADD muscle was normal. Mathematical modeling of oxidative ATP metabolism in muscle composed of three different fiber types indicated that the observed altered energy balance during submaximal exercise in VLCADD patients may be explained by a slow-to-fast shift in quadriceps fiber-type composition corresponding to 30% of the slow-twitch fiber-type pool in healthy quadriceps muscle. This study demonstrates for the first time that quadriceps energy balance during exercise in VLCADD patients is altered but not because of failing mitochondrial function. Our findings provide new clues to understanding the risk of rhabdomyolysis following exercise in human VLCADD.

Topics: Acetylcarnitine; Acyl-CoA Dehydrogenase, Long-Chain; Adenosine Triphosphate; Adolescent; Adult; Case-Control Studies; Congenital Bone Marrow Failure Syndromes; Exercise; Female; Humans; Lipid Metabolism, Inborn Errors; Male; Mitochondria; Mitochondrial Diseases; Models, Statistical; Muscle Fibers, Fast-Twitch; Muscle Fibers, Slow-Twitch; Muscular Diseases; Oxidative Phosphorylation; Phosphates; Phosphocreatine; Rhabdomyolysis

Systemic mitochondrial energy deficiency is implicated in the pathophysiology of many age-related human diseases. Currently available tools to estimate mitochondrial oxidative phosphorylation (OXPHOS) capacity in skeletal muscle in vivo lack high anatomic resolution. Muscle groups vary with respect to their contractile and metabolic properties. Therefore, muscle group-specific estimates of OXPHOS would be advantageous. To address this need, a noninvasive creatine chemical exchange saturation transfer (CrCEST) MRI technique has recently been developed, which provides a measure of free creatine. After exercise, skeletal muscle can be imaged with CrCEST in order to make muscle group-specific measurements of OXPHOS capacity, reflected in the recovery rate (τCr) of free Cr. In this study, we found that individuals with genetic mitochondrial diseases had significantly (

Topics: Adult; Creatine; Exercise Test; Female; Humans; Magnetic Resonance Imaging; Male; Middle Aged; Mitochondria, Muscle; Mitochondrial Diseases; Muscle, Skeletal; Oxidative Phosphorylation; Phosphocreatine; Phosphorylation

Mitochondrial dysfunction hypothetically contributes to neuronal degeneration in patients with Parkinson's disease. While several in vitro data exist, the measurement of cerebral mitochondrial dysfunction in living patients with Parkinson's disease is challenging. Anatomical magnetic resonance imaging combined with phosphorus and proton magnetic resonance spectroscopic imaging provides information about the functional integrity of mitochondria in specific brain areas. We measured partial volume corrected concentrations of low-energy metabolites and high-energy phosphates with sufficient resolution to focus on pathology related target areas in Parkinson's disease. Combined phosphorus and proton magnetic resonance spectroscopic imaging in the mesostriatal region was performed in 16 early and 13 advanced patients with Parkinson's disease and compared to 19 age-matched controls at 3 Tesla. In the putamen and midbrain of both Parkinson's disease groups, we found a bilateral reduction of high-energy phosphates such as adenosine triphophosphate and phosphocreatine as final acceptors of energy from mitochondrial oxidative phosphorylation. In contrast, low-energy metabolites such as adenosine diphophosphate and inorganic phosphate were within normal ranges. These results provide strong in vivo evidence that mitochondrial dysfunction of mesostriatal neurons is a central and persistent phenomenon in the pathogenesis cascade of Parkinson's disease which occurs early in the course of the disease.

Topics: Adenosine Triphosphate; Aged; Biomarkers; Brain; Brain Chemistry; Brain Diseases, Metabolic; Disease Progression; Energy Metabolism; Female; Humans; Magnetic Resonance Spectroscopy; Male; Middle Aged; Mitochondria; Mitochondrial Diseases; Oxidative Phosphorylation; Parkinson Disease; Phosphocreatine; Phosphorus; Predictive Value of Tests; Protons; Putamen; Substantia Nigra

Several lines of evidence support a potential role of skeletal muscle mitochondrial dysfunction in the pathogenesis of insulin resistance and/or type 2 diabetes. However, it remains to be established whether mitochondrial dysfunction represents either cause or consequence of the disease. We examined in vivo skeletal muscle mitochondrial function in early and advanced stages of type 2 diabetes, with the aim to gain insight in the proposed role of mitochondrial dysfunction in the aetiology of insulin resistance and/or type 2 diabetes.. Ten long-standing, insulin-treated type 2 diabetes patients, 11 subjects with impaired fasting glucose, impaired glucose tolerance and/or recently diagnosed type 2 diabetes, and 12 healthy, normoglycaemic controls, matched for age and body composition and with low habitual physical activity levels were studied. In vivo mitochondrial function of the vastus lateralis muscle was evaluated from post-exercise phosphocreatine (PCr) recovery kinetics using (31)P magnetic resonance spectroscopy (MRS). Intramyocellular lipid (IMCL) content was assessed in the same muscle using single-voxel (1)H MRS.. IMCL content tended to be higher in the type 2 diabetes patients when compared with normoglycaemic controls (P=0.06). The(31)P MRS parameters for mitochondrial function, i.e. PCr and ADP recovery time constants and maximum aerobic capacity, did not differ between groups.. The finding that in vivo skeletal muscle oxidative capacity does not differ between long-standing, insulin-treated type 2 diabetes patients, subjects with early stage type 2 diabetes and sedentary, normoglycaemic controls suggests that mitochondrial dysfunction does not necessarily represent either cause or consequence of insulin resistance and/or type 2 diabetes.

Topics: Adenosine Diphosphate; Blood Glucose; Diabetes Mellitus, Type 2; Glucose Intolerance; Humans; Insulin Resistance; Magnetic Resonance Spectroscopy; Middle Aged; Mitochondrial Diseases; Models, Biological; Muscle, Skeletal; Phosphocreatine; Phosphorus Isotopes; Prediabetic State; Severity of Illness Index

Topics: Adenosine Triphosphate; Bipolar Disorder; Brain; DNA, Mitochondrial; Humans; Hydrogen-Ion Concentration; Magnetic Resonance Imaging; Mitochondrial Diseases; Phosphocreatine

Huntington's disease (HD) is an autosomal dominantly inherited neurodegenerative disorder caused by a CAG repeat expansion in the IT-15 gene; however, it remains unknown how the mutation leads to selective neurodegeneration. Several lines of evidence suggest impaired mitochondrial function as a component of the neurodegenerative process in HD. We assessed energy metabolism in the skeletal muscle of 15 HD patients and 12 asymptomatic mutation carriers in vivo using 31P magnetic resonance spectroscopy. Phosphocreatine recovery after exercise is a direct measure of ATP synthesis and was slowed significantly in HD patients and mutation carriers in comparison to age- and gender-matched healthy controls. We found that oxidative function is impaired to a similar extent in manifest HD patients and asymptomatic mutation carriers. Our findings suggest that mitochondrial dysfunction is an early and persistent component of the pathophysiology of HD.

Topics: Adenosine Triphosphate; Adult; Case-Control Studies; Energy Metabolism; Exercise; Female; Humans; Huntingtin Protein; Huntington Disease; Immunohistochemistry; Magnetic Resonance Spectroscopy; Male; Middle Aged; Mitochondrial Diseases; Muscle, Skeletal; Mutation; Nerve Tissue Proteins; Nuclear Proteins; Phosphocreatine; Reaction Time

To examine the mitochondrial function in the myocardium after hemorrhagic shock and reperfusion and to evaluate the protective effect of urinary trypsin inhibitor (UTI) on mitochondria.. Animal experiment.. University research laboratory.. Wistar rats receiving 50,000 units/kg/hr of UTI (n = 27; UTI group) and control rats (n = 26; control group).. Rats were subjected to low-perfusion ischemia with the left ventricular systolic pressure maintained at 50 mm Hg for 60 mins by bleeding, followed by a 60-min reperfusion by transfusion of shed blood. UTI was infused continuously from 10 mins before bleeding. Cardiac function was measured before bleeding, after bleeding, and after transfusion; at each determination point, the myocardial contents of adenosine triphosphate (ATP), creatine phosphate (P-Cr), pyruvate (Pyr), and lactate (Lac) were measured enzymatically. The cytosolic phosphorylation potential (PP) as well as the redox potential of the oxidized form of nicotinamide adenine dinucleotide/reduced form of nicotinamide adenine dinucleotide couple in mitochondria (Eh(NAD+/NADH)) and change of Gibbs free energy in ATP hydrolysis (deltaG(ATP hydrolysis) energy) were calculated.. Cardiac function decreased during hemorrhagic shock but improved significantly in the UTI group after transfusion compared with the control group. Lac and the Lac/Pyr ratio were significantly lower in the UTI group than in the control group after transfusion. ATP and P-Cr were significantly higher in the UTI group than in the control group after transfusion. PP (x10(3) M-1), Eh(NAD+/NADH) (x - 1 mV), and deltaG(ATP hydrolysis) (x - 1 kcal/mol) were 1.9 +/- 0.4, 266 +/- 4, and 9.7 +/- 0.2, respectively, in the control group and 4.0 +/- 0.9, 274 +/- 5 and 13.0 +/- 0.2, respectively, in the UTI group after transfusion (p <.001, p <.001, and p <.001, respectively).. In reperfusion after hemorrhagic shock, oxidative phosphorylation in myocardial mitochondria is impaired and energy production remains reduced, even after reperfusion. UTI contributed to the recovery of cardiac function after reperfusion, probably by reducing the severity of mitochondrial dysfunction during a state of shock and by maintaining energy production.

Topics: Adenosine Triphosphate; Animals; Blood Pressure; Blood Transfusion, Autologous; Energy Metabolism; Glycoproteins; Heart Rate; Lactic Acid; Male; Mitochondria, Heart; Mitochondrial Diseases; Myocardial Reperfusion Injury; Oxidation-Reduction; Phosphocreatine; Pyruvic Acid; Rats; Rats, Wistar; Shock, Hemorrhagic; Stroke Volume

Reperfusion injury is believed to contribute to the pathophysiology of ischemic cell death, but the precipitating factors have yet to be completely elucidated. The goal of this study was to examine if reflow-induced secondary energy failure is a component in the events that lead to cell death following increasing periods of middle cerebral artery (MCA) occlusion in Wistar rats. Discrete sections within the MCA distribution were dissected and analyzed for high-energy phosphates and glucose. Regional cerebral blood flow was determined by [14C]-iodoantipyrine technique in representative groups. The levels of ATP + P-creatine were initially depressed at the end of the focal ischemia and the concentrations in the penumbra were unchanged for up to 8 h after 2 h of ischemia which contrasts with response in the ischemic core, striatum, and penumbra where the HEP generally recovered to values near those of control only to decrease with increasing periods of reflow. The possibility of a rebound ischemia in secondary energy failure (SEF) was precluded by regional CBF values and concentrations of glucose that were significantly higher than the threshold for an ischemic effect. The depletion of cellular energy stores following SEF strongly indicates that the evolution of infarct during reflow results from loss of ATP and its synthesis.

Topics: Adenosine Triphosphate; Animals; Brain Ischemia; Cell Death; Cerebrovascular Circulation; Energy Metabolism; Infarction, Middle Cerebral Artery; Male; Mitochondrial Diseases; Nerve Degeneration; Phosphocreatine; Rats; Rats, Wistar; Reperfusion Injury; Telencephalon