phosphocreatine and Muscular-Atrophy

Weight loss and low BMI due to an underlying illness have been associated with increased mortality, reduced functional capacity, and diminished quality of life. There is a need for well tolerated, long-term approaches to maintain body weight in patients with cachexia or wasting. The purpose of this review is to highlight the scientific and clinical evidence derived from the recent literature investigating the rationale for and potential medical use of creatine supplementation in patients with cachexia or wasting.. Some studies have demonstrated that supplementation with creatine can increase creatine reserves in skeletal muscle and increase muscle mass and performance in various disease states that affect muscle size and function. The mechanisms underlying these effects are not clear. It has been suggested that creatine supplementation may increase intramuscular phosphocreatine stores and promote more rapid recovery of adenosine triphosphate levels following exercise, thus allowing users to exercise for longer periods or at higher intensity levels. Other hypothesized mechanisms include attenuation of proinflammatory cytokines, stimulation of satellite cell proliferation and upregulation of genes that promote protein synthesis and cell repair.. Creatine is a generally well tolerated, low-cost, over-the-counter nutritional supplement that shows potential in improving lean body mass and functionality in patients with wasting diseases. However, placebo-controlled studies have shown variable effects, with improvements in some and not in others. Additional studies with longer follow-up are required to identify the populations that might benefit most from creatine supplementation.

Topics: Adenosine Triphosphate; Body Composition; Cachexia; Creatine; Dietary Supplements; Exercise; Humans; Muscle, Skeletal; Muscular Atrophy; Phosphocreatine; Wasting Syndrome

Nuclear magnetic resonance spectroscopy has progressed far since the original description of the phenomenon (30,31) and now permits noninvasive and harmless measurements to be repeatedly made of tissue biochemistry. Currently, there is a paucity of NMR data on normal human metabolism and the interpretation of spectra recorded from diseased tissues must be circumspect. This is further complicated by the inability of NMR spectroscopy to render accurate quantitative measurements and all observations must be considered to be compatible with, rather than diagnostic of, specific diseases. Nevertheless, NMR is an important addition to the clinician's armamentarium and these relatively expensive instruments should be situated in regional referral centres. Undoubtedly the most significant advances in NMR will only occur following the successful combination of the imaging and spectroscopic techniques, since that will enable anatomical and metabolic data to be obtained from a single site without the need for biopsy. Nuclear magnetic resonance spectroscopy has much to offer and the practical hazards appear to be few. In the next few years we will undoubtedly see an improvement in the quality of the data obtainable an a growing diversity of clinical applications.

Topics: Humans; Hypoxia, Brain; Magnetic Resonance Spectroscopy; Muscles; Muscular Atrophy; Muscular Diseases; Neoplasms; Phosphates; Phosphocreatine; Phosphofructokinase-1

Topics: Actomyosin; Adenosine Triphosphate; Animals; Cell Membrane; Creatine; Creatine Kinase; Energy Metabolism; Humans; Hyperparathyroidism, Secondary; Muscles; Muscular Atrophy; Oxidative Phosphorylation; Oxygen Consumption; Phosphocreatine; Rabbits; Rats; Troponin; Troponin C; Uremia; Vitamin D Deficiency

Skeletal muscle mitochondrial oxidative capacity declines with age and negatively affects walking performance, but the mechanism for this association is not fully clear. We tested the hypothesis that impaired oxidative capacity affects muscle performance and, through this mechanism, has a negative effect on walking speed. Muscle mitochondrial oxidative capacity was measured by in vivo phosphorus magnetic resonance spectroscopy as the postexercise phosphocreatine resynthesis rate, k

Topics: Adult; Aged; Aged, 80 and over; Aging; Baltimore; Cross-Sectional Studies; Energy Metabolism; Female; Humans; Longitudinal Studies; Male; Middle Aged; Mitochondria; Muscle Strength; Muscle, Skeletal; Muscular Atrophy; Phosphocreatine; Walking

Muscle disuse induces a wide array of structural, biochemical, and neural adaptations in skeletal muscle, which can affect its function. We recently demonstrated in patients with an orthopedic injury that cast immobilization alters the resting P(i) content of skeletal muscle, which may contribute to loss of specific force. The goal of this study was to determine the direct effect of disuse on the basal phosphate content in skeletal muscle in an animal model, avoiding the confounding effects of injury/surgery. (31)P and (1)H MRS data were acquired from the gastrocnemius muscle of young adult mice (C57BL6 female, n = 8), at rest and during a reversible ischemia experiment, before and after 2 weeks of cast immobilization. Cast immobilization resulted in an increase in resting P(i) content (75%; p < 0.001) and the P(i) to phosphocreatine (PCr) ratio (P(i)/PCr; 80%, p < 0.001). The resting concentrations of ATP, PCr and total creatine (PCr + creatine) and the intracellular pH were not significantly different after immobilization. During ischemia (30 min), PCr concentrations decreased to 54 +/- 2% and 52 +/- 6% of the resting values in pre-immobilized and immobilized muscles, respectively, but there were no detectable differences in the rates of P(i) increase or PCr depletion (0.55 +/- 0.01 mM min(-1) and 0.52 +/- 0.03 mM min(-1) before and after immobilization, respectively; p = 0.78). At the end of ischemia, immobilized muscles had a twofold higher phosphorylation potential ([ADP][P(i)]/[ATP]) and intracellular buffering capacity (3.38 +/- 0.54 slykes vs 6.18 +/- 0.57 slykes). However, the rate of PCr resynthesis (k(PCr)) after ischemia, a measure of in vivo mitochondrial function, was significantly lower in the immobilized muscles (0.31 +/- 0.04 min(-1)) than in pre-immobilized muscles (0.43 +/- 0.04 min(-1)). In conclusion, our findings indicate that 2 weeks of cast immobilization, independent of injury-related alterations, leads to a significant increase in the resting P(i) content of mouse skeletal muscle. The increase in P(i) with muscle disuse has a significant effect on the cytosolic phosphorylation potential during transient ischemia and increases the intracellular buffering capacity of skeletal muscle.

Topics: Adenosine Triphosphate; Animals; Female; Hindlimb; Hindlimb Suspension; Ischemia; Magnetic Resonance Spectroscopy; Mice; Mice, Inbred Strains; Mitochondria, Muscle; Muscle Weakness; Muscle, Skeletal; Muscular Atrophy; Phosphates; Phosphocreatine; Phosphorylation; Protons; Rest

The purpose of this feasibility study was to demonstrate non-invasive metabolic imaging of human muscular atrophy using significant changes of NMR signals that are related directly or indirectly to fiber necrosis.. Single-voxel (1)H NMR spectroscopy and two-dimensional (31)P spectroscopic imaging on a 1.5-T whole-body scanner were used for in vivo mapping of areas of muscle damage in two cases of differently localized and pronounced atrophy. Spectral patterns affiliated with severe and intermediate stages of degeneration were compared to data of healthy control tissue to derive appropriate metabolic markers related to lipid infiltration or high-energy (31)P metabolism.. Reliable detection of atrophic tissue was achieved by the following parameters: (1) liposclerotic turnover is related to a drastic reduction in the water/lipid (1)H signal intensity ratio (up to a factor of 74 compared to adjacent healthy tissue); (2) the (31)P resonance of phosphocreatine (PCr) is an adequate marker for differentiation of intact myocells with high-energy metabolism from regions dominated by terminal fiber necrosis (PCr signal vanished nearly completely or intensity was reduced by a factor of 3 in affected muscles). Metabolic images based on this signal allowed accurate non-invasive localization of atrophic tissue.. The molecular information provided by NMR spectroscopy--previously only used with poor localization in atrophy studies--enables access to both the myocell-specific high-energy metabolism and the result of lipid infiltration allowing non-invasive mapping of degenerate tissue. The ability to investigate the results of these advanced levels of atrophy would also be useful for studies of more subtle degrees of denervation.

Topics: Choline; Feasibility Studies; Humans; Lipid Metabolism; Magnetic Resonance Spectroscopy; Male; Middle Aged; Muscular Atrophy; Phosphocreatine; Taurine

Animal models are valuable research tools towards effective prevention of sarcopenia and towards a better understanding of the mechanisms underlying skeletal muscle aging. We investigated whether senescence-accelerated mouse (SAM) strains provide valid models for skeletal muscle aging studies. Male senescence-prone mice SAMP6 and SAMP8 were studied at age 10, 25 and 60 weeks and compared with senescence-resistant strain, SAMR1. Soleus and EDL muscles were tested for in vitro contractile properties, phosphocreatine content, muscle mass and fiber-type distribution. Declined muscle mass and contractility were observed at 60 weeks, the differences being more pronounced in SAMP8 than SAMP6 and more pronounced in soleus than EDL. Likewise, age-related decreases in muscle phosphocreatine content and type-II fiber size were most pronounced in SAMP8 soleus. In conclusion, typical features of muscular senescence occur at relatively young age in SAMP8 and nearly twice as fast as compared with other models. We suggest that soleus muscles of SAMP8 mice provide a cost-effective model for muscular aging studies.

Topics: Aging; Animals; Body Weight; Male; Mice; Mice, Inbred Strains; Models, Animal; Muscle Contraction; Muscle Fatigue; Muscle Fibers, Skeletal; Muscle, Skeletal; Muscular Atrophy; Organ Size; Phosphocreatine; Survival Analysis

Muscle dysfunction, which contributes to morbidity in patients on haemodialysis, has several manifestations and a number of possible causes. We applied the non-invasive techniques of (31)P-magnetic resonance spectroscopy ((31)P-MRS), magnetic resonance imaging (MRI) and near-infrared spectroscopy (NIRS) to calf muscle of dialysed patients to define the abnormalities in muscle cross-sectional area (CSA), contractile efficiency, mitochondrial function and vascular O(2) supply.. We performed (31)P-MRS/NIRS/MRI studies on the lateral gastrocnemius during isometric plantarflexion and recovery in 23 male patients on haemodialysis (age 24-71 years; haemoglobin 9.9-14.2 g/dl; bicarbonate 17-30 mmol/l; urea reduction ratio 53-77%; parathyroid hormone 1-95 U/l) and 15 male controls (age 29-71 years). To understand the relationships between calf CSA and body mass we also performed MRI only in a further six male patients and 18 male controls.. In patients, exercise duration was 30+/-11% lower than in controls. Muscle CSA was lower by 26+/-5%, but contractile efficiency (force/CSA/ATP turnover) was normal. Slowing of post-exercise phosphocreatine (PCr) recovery implied a 22+/-5% defect in effective 'mitochondrial capacity'. That PCr recovery was slow relative to NIRS recovery suggests that this is largely an intrinsic mitochondrial problem (not the result of impaired O(2) supply), one which, furthermore, correlated with CSA. Urea reduction ratio showed a negative correlation with body mass and CSA, but none with PCr rate constant.. The relationships to urea reduction ratio reflect the effect of muscle mass on dialysis efficiency, rather than direct effects on muscle CSA or metabolism. The relationship between PCr recovery and calf CSA suggests a role for the mitochondrial defect, whatever its cause, in the development of muscle wasting, although a common cause (e.g. physical inactivity) for both abnormalities cannot be ruled out.

Topics: Humans; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Male; Mitochondria, Muscle; Muscle Contraction; Muscle, Smooth; Muscular Atrophy; Phosphocreatine; Phosphorus Isotopes; Renal Dialysis; Spectroscopy, Near-Infrared

Topics: Adenosine Triphosphate; Energy Metabolism; Exercise Therapy; Humans; Kidney Failure, Chronic; Lactic Acid; Leg; Muscular Atrophy; Oxygen; Phosphocreatine; Renal Dialysis; Self Care

We studied the effects of denervation on the energy metabolism and peripheral circulation dynamics of rat hindlimb muscles during and after exercise. The sciatic nerves of male Wistar rats were cut to produce denervation. Energy metabolism was assessed by phosphorus-31 magnetic resonance spectroscopy (MRS), and circulation by fluorine-19 MRS. Exercise of rat hindlimb muscles was induced by electrical stimulation at 40 Hz. The inorganic phosphate (Pi) / ¿Pi + phosphocreatine (PCr)¿ ratio, an indicator of the energy level, was 0.795 immediately after denervation. The ratios 4 and 8 weeks after denervation were 0.870 and 0.853, respectively. The intracellular pH during the 4 min after initiation of stimulation was significantly reduced 4 and 8 weeks after denervation compared with the value immediately after denervation. The signal strength of the research perfluoro-carbon (FC-43; perfluorotributylamine) a measure of circulation dynamics, increased to 167% in controls during exercise, but an increase of only 134% was seen in rats 8 weeks after denervation. These results showed that the energy supply and circulation dynamics in denervated atrophic muscles decreased during exercise compared with findings in control muscles.

Topics: Animals; Blood Substitutes; Denervation; Electric Stimulation; Energy Metabolism; Fluorine Radioisotopes; Fluorocarbons; Follow-Up Studies; Hindlimb; Hydrogen-Ion Concentration; Isometric Contraction; Magnetic Resonance Spectroscopy; Male; Muscle, Skeletal; Muscular Atrophy; Organ Size; Phosphates; Phosphocreatine; Phosphorus Isotopes; Physical Exertion; Radiopharmaceuticals; Rats; Rats, Wistar; Regional Blood Flow; Sciatic Nerve

Skeletal muscle energetics of seven hyperthyroid patients were investigated throughout a rest-exercise-recovery protocol using phosphorus-31 magnetic resonance spectroscopy (31P MRS) to quantitatively document in vivo the metabolic bases of impaired muscle performance in hyperthyroidism. The contributions of the main pathways of adenosine triphosphate (ATP) synthesis to energy production and proton efflux were measured and compared with results from normal muscle. At rest, a reduced concentration of phosphocreatine (PCr) was calculated for hyperthyroid patients when compared with controls, whereas pH and concentrations of inorganic phosphate (Pi) and phosphomonoesters (PME) were not different from controls. During exercise, the analysis of changes in pH and PCr concentration demonstrated that (1) at the onset of exercise, the magnitude of glycolysis activation is significantly larger for patients, resulting in a marked pH decrease; (2) the energy cost of exercise is higher for patients as compared with controls performing the same amount of work; and (3) both anaerobic and aerobic pathways are significantly more activated in the hyperthyroid group throughout the 3 minutes of exercise. During recovery, the rates of proton efflux and PCr resynthesis were similar in both groups, excluding any alteration in oxidative function and proton handling as a cause of initial glycolytic hyperactivation. The increased energy cost measured for patients during exercise evidences an increased need for energy, which is (1) probably linked to the existence of additional ATP-consuming mechanism(s), and (2) supported by hyperactivation of both aerobic and anaerobic pathways. These findings imply that, all things equal, a hyperthyroid muscle requires more energy to function than normal, and as a result is potentially more fatiguable.

Topics: Adolescent; Adult; Energy Metabolism; Female; Humans; Hyperthyroidism; Magnetic Resonance Spectroscopy; Male; Middle Aged; Muscle, Skeletal; Muscular Atrophy; Phosphocreatine; Phosphorus; Physical Exertion; Reproducibility of Results; Rest

Responses of high-energy phosphates and metabolic properties to hindlimb suspension were studied in adult rats. The relative content of phosphocreatine (PCr) in the calf muscles was significantly higher in rats suspended for 10 days than in age-matched cage controls. The Pi/PCr ratio, where Pi is inorganic phosphate, in suspended muscles was less than controls. The absolute weights of soleus and medial gastrocnemius (MG) were approximately 40% less than controls. Although the % fiber distribution in MG was unchanged, the % slow fibers decreased and the % fibers which were classified as both slow and fast was increased in soleus. The activities (per unit weight or protein) of succinate dehydrogenase and lactate dehydrogenase in soleus were unchanged but those of cytochrome oxidase, beta-hydroxyacyl CoA dehydrogenase, and citrate synthase were decreased following unloading. None of these enzyme activities in MG changed. However, the total levels of all enzymes in whole muscles decreased by suspension. It is suggested that shift of slow muscle toward fast type by unloading is associated with a decrease in mitochondrial biogenesis. Further, gravitational unloading affected the levels of muscle proteins differently even in the same mitochondrial enzymes.

Topics: Animals; Hindlimb Suspension; Male; Mitochondria, Muscle; Muscle Fibers, Fast-Twitch; Muscle Fibers, Slow-Twitch; Muscle, Skeletal; Muscular Atrophy; Myosins; Phosphates; Phosphocreatine; Rats; Rats, Wistar

The atrophy, reinnervation, and metabolism of free muscle flaps were studied in a rat model, by syngeneic and orthotopic transplantation of abdominal wall muscle flaps with neurovascular anastomoses. The three parameters were examined at different time periods, using electrophysiologic and 31-P-spectroscopic measurements. Results show that a certain degree of atrophy (one-fifth of the original volume) must be expected, even when new axons grow throughout the nerve. This is explained by the early reduction of flap metabolism, leading to a loss of parenchyma until neuromuscular conduction is restored. As the maximum duration of ischemia is 2 hr, muscular damage due to reduced metabolism was not produced.

Topics: Abdominal Muscles; Adenosine Triphosphate; Animals; Axons; Magnetic Resonance Spectroscopy; Male; Muscle Contraction; Muscular Atrophy; Nerve Regeneration; Phosphocreatine; Rats; Rats, Inbred Lew; Surgical Flaps

The purpose of this study was to investigate the prevalence of skeletal muscle atrophy and its relation to exercise intolerance and abnormal muscle metabolism in patients with heart failure (HF).. Peak VO2, percent ideal body weight (% IBW), 24-hour urine creatinine (Cr), and anthropometrics were measured in 62 ambulatory patients with HF. 31P magnetic resonance spectroscopy (MRS) and imaging (MRI) of the calf were performed in 15 patients with HF and 10 control subjects. Inorganic phosphorus (Pi), phosphocreatine (PCr), and intracellular pH were measured at rest and during exercise. Calf muscle volume was determined from the sum of the integrated area of muscle in 1-cm-thick contiguous axial images from the patella to the calcaneus. A reduced skeletal muscle mass was noted in 68% of patients, as evidenced by a decrease in Cr-to-height ratio of less than 7.4 mg/cm and/or upper arm circumference of less than 5% of normal. Calf muscle volume (MRI) was also reduced in the patients with HF (controls, 675 +/- 84 cm3/m2; HF, 567 +/- 112 cm3/m2; p less than 0.05). Fat stores were largely preserved with triceps skinfold of less than 5% of normal and/or IBW of less than 80% in only 8% of patients. Modest linear correlations were observed between peak VO2 and both calf muscle volume per meter squared (r = 0.48) and midarm muscle area (r = 0.36) (both p less than 0.05). 31P metabolic abnormalities during exercise were observed in the patients with HF, which is consistent with intrinsic oxidative abnormalities. The metabolic changes were weakly correlated with muscle volume (r = -0.42, p less than 0.05).. These findings indicate that patients with chronic HF frequently develop significant skeletal muscle atrophy and metabolic abnormalities. Atrophy contributes modestly to both the reduced exercise capacity and altered muscle metabolism.

Topics: Exercise; Exercise Test; Female; Heart Failure; Humans; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Male; Middle Aged; Muscles; Muscular Atrophy; Phosphocreatine; Phosphorus; Prevalence

Intact as well as neuromuscular affected skeletal muscles can be precisely analysed by MR tomography with high magnetic field strengths. The substitution of muscle by adipose tissue under atrophic conditions is seen most clearly in fat images, while the morphology of small structures is predominantly shown by water images. The aim of in-vivo spectroscopy is an identification and quantification of metabolites. A relative increase in the amount of adipose tissue within atrophic muscles was confirmed by the 1-H spectrum. As concluded from 13-C and 31-P spectra there was neither a change in adipose tissue composition nor a modification of energy metabolism.

Topics: Adenosine Triphosphate; Humans; Magnetic Resonance Spectroscopy; Muscular Atrophy; Muscular Diseases; Muscular Dystrophies; Phosphates; Phosphocreatine

Topics: Adenosine Triphosphate; Animals; Body Weight; Cortisone; Creatine; Creatine Kinase; Diuresis; Fructose-Bisphosphate Aldolase; Male; Muscles; Muscular Atrophy; Phosphocreatine; Phosphorus; Potassium Chloride; Potassium Deficiency; Rabbits