phosphocreatine and Muscle-Weakness

In recent years, COPD has become increasingly thought of as a systemic disease affecting many tissues and organs in addition to the lungs. The skeletal muscles in particular have been the target of much research focusing on whether the universally observed exercise limitation reflects a systemic myopathic effect of COPD, or simply the consequences of extreme, long-term inactivity. In this paper, the evidence is reviewed for COPD patients without loss of muscle mass and who are not taking systemic steroids. While altered levels of antioxidant defences (lower), circulating inflammatory biomarkers (higher) and anabolic hormones (lower) have been found in COPD, cause and effect remains to be established for the link of inflammation/oxidative stress to muscle dysfunction. Other evidence used to propose a myopathic state (early lactate release, reduced power output, lower metabolic enzyme capacities, greater phosphocreatine breakdown and slower phosphocreatine restoration after exercise, and altered fibre type distribution) also occur in normal subjects who are extremely inactive. Furthermore, intense small muscle mass training can normalize small muscle function in these patients. Based on these data, it remains to be shown that the muscles in COPD patients without loss of muscle mass are myopathic. The interesting discussion about systemic effects of COPD should not get in the way of systematic muscle training, which has been shown to be an effective component of rehabilitation.

Topics: Exercise Therapy; Forced Expiratory Volume; Humans; Insulin-Like Growth Factor I; Interleukin-6; Lactates; Muscle Weakness; Muscle, Skeletal; Muscular Diseases; Oxidative Stress; Phosphocreatine; Physical Fitness; Pulmonary Disease, Chronic Obstructive; Pulmonary Ventilation; Testosterone; Tumor Necrosis Factor-alpha

To test the hypothesis that oral creatine supplements with exercise are more effective than exercise alone in improving muscle function in patients with established dermatomyositis or polymyositis receiving chronic medical therapies who are clinically weak yet stable.. In a 6-month, 2-center, double-blind, randomized controlled trial, patients were randomized to receive oral creatine supplements (8 days, 20 gm/day then 3 gm/day) or placebo. All patients followed a home exercise program. The primary outcome was aggregate functional performance time (AFPT), reflecting the ability to undertake high-intensity exercise. Secondary outcomes included a functional index measuring endurance and muscle bioenergetics on (31)P magnetic resonance spectroscopy ((31)P MRS). Patients were receiving stable immunosuppressive treatment and/or corticosteroids.. A total of 37 patients with polymyositis or dermatomyositis were randomized (19 to creatine, 18 to placebo); 29 completed 6 months. Intent-to-treat analyses demonstrated that AFPT improved significantly at 6 months with creatine (median decrease 13%, range -32-8%) compared with placebo (median decrease 3%, range -13-16%; P = 0.029 by Mann-Whitney U test). A completer analysis also showed significant benefits from creatine (P = 0.014). The functional index improved significantly with both creatine and placebo (P < 0.05 by paired Wilcoxon's rank sum test), with a significant benefit between groups in the completer analysis only. Phosphocreatine/beta-nucleoside triphosphate ratios using MRS increased significantly in the creatine group (P < 0.05) but not in the control group. No clinically relevant adverse events were associated with creatine.. Oral creatine supplements combined with home exercises improve functional performance without significant adverse effects in patients with polymyositis or dermatomyositis. They appear safe, effective, and inexpensive.

Topics: Administration, Oral; Creatine; Double-Blind Method; Energy Metabolism; Exercise; Female; Humans; Magnetic Resonance Spectroscopy; Male; Middle Aged; Muscle Strength; Muscle Weakness; Myositis; Phosphocreatine; Phosphorus Isotopes; Placebos; Treatment Outcome

Creatine monohydrate (CrM) supplementation may increase strength in some types of muscular dystrophy. A recent study in myotonic muscular dystrophy type 1 (DM1) did not find a significant treatment effect, but measurements of muscle phosphocreatine (PCr) were not performed. We completed a randomized, double-blind, cross-over trial using 34 genetically confirmed adult DM1 patients without significant cognitive impairment. Participants received CrM (5 g, approximately 0.074 g/kg daily) and a placebo for each 4-month phase with a 6-week wash-out. Spirometry, manual muscle testing, quantitative isometric strength testing of handgrip, foot dorsiflexion, and knee extension, handgrip and foot dorsiflexion endurance, functional tasks, activity of daily living scales, body composition (total, bone, and fat-free mass), serum creatine kinase activity, serum creatinine concentration and clearance, and liver function tests were completed before and after each intervention, and muscle PCr/beta-adenosine triphosphate (ATP) ratios of the forearm flexor muscles were completed at the end of each phase. CrM supplementation did not increase any of the outcome measurements except for plasma creatinine concentration (but not creatinine clearance). Thus, CrM supplementation at 5 g daily does not have any effects on muscle strength, body composition, or activities of daily living in patients with DM1, perhaps because of a failure of the supplementation to increase muscle PCr/beta-ATP content.

Topics: Activities of Daily Living; Adult; Body Mass Index; Creatine; Cross-Over Studies; Exercise Tolerance; Female; Humans; Magnetic Resonance Spectroscopy; Male; Middle Aged; Muscle Proteins; Muscle Weakness; Muscle, Skeletal; Myotonic Dystrophy; Phosphocreatine; Respiratory Function Tests; Treatment Failure

The effect of a six-month peritoneal amino acid administration on muscle metabolism at rest and during exercise was examined in 12 patients (4 control and 8 amino acid treated) on continuous ambulatory peritoneal dialysis. 31P-magnetic resonance spectroscopy was used to measure several high-energy phosphates (PCr, Pi) in resting muscle and during exercise and recovery. At rest, no significant changes were detected between the non-treated (control) and the amino acid treated (experimental) group. Before the administration of amino acids, the exercise-induced fall in [PCr], the increase in [ADP] and [Pi] and the pH were not significantly different in the control and experimental group. The initial rate of PCr recovery and the calculated maximal rate of ATP-synthesis (Qmax) for the control subjects was not significantly different at the onset and the end of the study. In the treated group, however, the fall in [PCr] and increase in [ADP] after exercise were significantly lower after than before treatment, while [Pi] and pH were identical. The initial rate of PCr recovery and Qmax were also significantly improved. These changes indicate an improved oxidative phosphorylation under the treatment and suggest that the impaired oxidative metabolism of the dialysis patients could be the result of their bad nutritional state.

Topics: Adenosine Diphosphate; Adenosine Triphosphate; Aged; Aged, 80 and over; Amino Acids; Dialysis Solutions; Female; Humans; Hydrogen-Ion Concentration; Kinetics; Magnetic Resonance Spectroscopy; Male; Middle Aged; Muscle Weakness; Muscles; Peritoneal Dialysis, Continuous Ambulatory; Phosphates; Phosphocreatine; Phosphorus Isotopes; Phosphorylation; Uremia

Muscle weakness in the elderly has been linked to recurrent falls and morbidity; therefore, elucidating the mechanisms contributing to the loss of muscle function and mobility with advancing age is critical. To this aim, we comprehensively examined skeletal muscle metabolic function and hemodynamics in 11 young (23 ± 2 years), 11 old (68 ± 2 years), and 10 oldest-old (84 ± 2 years) physical activity-matched participants. Specifically, oxidative stress markers, mitochondrial function, and the ATP cost of contraction as well as peripheral hemodynamics were assessed during dynamic plantar flexion exercise at 40 per cent of maximal work rate (WRmax). Both the PCr recovery time constant and the peak rate of mitochondrial ATP synthesis were not significantly different between groups. In contrast, the ATP cost of dynamic contractions (young: 1.5 ± 1.0, old: 3.4 ± 2.1, oldest-old: 6.1 ± 3.6 mM min-1 W-1) and systemic markers of oxidative stress were signficantly increased with age, with the ATP cost of contraction being negatively correlated with WRmax (r = .59, p < .05). End-of-exercise blood flow per Watt rose significantly with increasing age (young: 37 ± 20, old: 82 ± 68, oldest-old: 154 ± 93 mL min-1 W-1). These findings suggest that the progressive deterioration of muscle contractile efficiency with advancing age may play an important role in the decline in skeletal muscle functional capacity in the elderly.

Topics: Adenosine Triphosphate; Adult; Aged; Aged, 80 and over; Aging; Exercise; Female; Hemodynamics; Humans; Kinetics; Male; Mitochondria, Muscle; Muscle Contraction; Muscle Weakness; Muscle, Skeletal; Oxidative Stress; Phosphocreatine; Young Adult

The interleukin-10 knockout mouse (IL10(tm/tm)) has been proposed as a model for human frailty, a geriatric syndrome characterized by skeletal muscle (SM) weakness, because it develops an age-related decline in SM strength compared to control (C57BL/6J) mice. Compromised energy metabolism and energy deprivation appear to play a central role in muscle weakness in metabolic myopathies and muscular dystrophies. Nonetheless, it is not known whether SM energy metabolism is altered in frailty. A combination of in vivo (31)P nuclear magnetic resonance experiments and biochemical assays was used to measure high-energy phosphate concentrations, the rate of ATP synthesis via creatine kinase (CK), the primary energy reserve reaction in SM, as well as the unidirectional rates of ATP synthesis from inorganic phosphate (Pi) in hind limb SM of 92-week-old control (n = 7) and IL10(tm/tm) (n = 6) mice. SM Phosphocreatine (20.2 ± 2.3 vs. 16.8 ± 2.3 μmol/g, control vs. IL10(tm/tm), p < 0.05), ATP flux via CK (5.0 ± 0.9 vs. 3.1 ± 1.1 μmol/g/s, p < 0.01), ATP synthesis from inorganic phosphate (Pi → ATP) (0.58 ± 0.3 vs. 0.26 ± 0.2 μmol/g/s, p < 0.05) and the free energy released from ATP hydrolysis (∆G ∼ATP) were significantly lower and [Pi] (2.8 ± 1.0 vs. 5.3 ± 2.0 μmol/g, control vs. IL10(tm/tm), p < 0.05) markedly higher in IL10(tm/tm) than in control mice. These observations demonstrate that, despite normal in vitro metabolic enzyme activities, in vivo SM ATP kinetics, high-energy phosphate levels and energy release from ATP hydrolysis are reduced and inorganic phosphate is elevated in a murine model of frailty. These observations do not prove, but are consistent with the premise, that energetic abnormalities may contribute metabolically to SM weakness in this geriatric syndrome.

Topics: Adenosine Triphosphate; Aging; Animals; Creatine Kinase; Disease Models, Animal; Energy Metabolism; Hydrolysis; Kinetics; Magnetic Resonance Spectroscopy; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Muscle Weakness; Muscle, Skeletal; Phenotype; Phosphocreatine

Mice, whose ribosomal protein S6 cannot be phosphorylated due to replacement of all five phosphorylatable serine residues by alanines (rpS6(P-/-)), are viable and fertile. However, phenotypic characterization of these mice and embryo fibroblasts derived from them, has established the role of these modifications in the regulation of the size of several cell types, as well as pancreatic beta-cell function and glucose homeostasis. A relatively passive behavior of these mice has raised the possibility that they suffer from muscle weakness, which has, indeed, been confirmed by a variety of physical performance tests.. A large variety of experimental methodologies, including morphometric measurements of histological preparations, high throughput proteomic analysis, positron emission tomography (PET) and numerous biochemical assays, were used in an attempt to establish the mechanism underlying the relative weakness of rpS6(P-/-) muscles. Collectively, these experiments have demonstrated that the physical inferiority appears to result from two defects: a) a decrease in total muscle mass that reflects impaired growth, rather than aberrant differentiation of myofibers, as well as a diminished abundance of contractile proteins; and b) a reduced content of ATP and phosphocreatine, two readily available energy sources. The abundance of three mitochondrial proteins has been shown to diminish in the knockin mouse. However, the apparent energy deficiency in this genotype does not result from a lower mitochondrial mass or compromised activity of enzymes of the oxidative phosphorylation, nor does it reflect a decline in insulin-dependent glucose uptake, or diminution in storage of glycogen or triacylglycerol (TG) in the muscle.. This study establishes rpS6 phosphorylation as a determinant of muscle strength through its role in regulation of myofiber growth and energy content. Interestingly, a similar role has been assigned for ribosomal protein S6 kinase 1, even though it regulates myoblast growth in an rpS6 phosphorylation-independent fashion.

Topics: Adenosine Triphosphate; Animals; Energy Metabolism; Glucose; Glycogen; Insulin; Mice; Mitochondria; Muscle Contraction; Muscle Fibers, Skeletal; Muscle Weakness; Muscle, Skeletal; Organ Size; Oxidative Phosphorylation; Phosphocreatine; Ribosomal Protein S6; Signal Transduction; Triglycerides

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

Glycogen storage disease type II (GSD II) is an inherited progressive muscle disease in which lack of functional acid alpha-glucosidase (AGLU) results in lysosomal accumulation of glycogen. We report on the impact of a null mutation of the acid alpha-glucosidase gene (AGLU(-/-)) in mice on the force production capabilities, contractile mass, oxidative capacity, energy status, morphology, and desmin content of skeletal muscle. Muscle function was assessed in halothane-anesthetized animals, using a recently designed murine isometric dynamometer. Maximal torque production during single tetanic contraction was 50% lower in the knockout mice than in wild type. Loss of developed torque was found to be disproportionate to the 20% loss in muscle mass. During a series of supramaximal contraction, fatigue, expressed as percentile decline of developed torque, did not differ between AGLU(-/-) mice and age-matched controls. Muscle oxidative capacity, energy status, and protein content (normalized to either dry or wet weight) were not changed in knockout mice compared to control. Alterations in muscle cell morphology were clearly visible. Desmin content was increased, whereas alpha-actinin was not. As the decline in muscle mass is insufficient to explain the degree in decline of mechanical performance, we hypothesize that the large clusters of noncontractile material present in the cytoplasm hamper longitudinal force transmission, and hence muscle contractile function. The increase in muscular desmin content is most likely reflecting adaptations to altered intracellular force transmission.

Topics: Actinin; Adenosine Diphosphate; Adenosine Monophosphate; Adenosine Triphosphate; alpha-Glucosidases; Animals; Body Weight; Desmin; Glucan 1,4-alpha-Glucosidase; Glycogen; Glycogen Storage Disease Type II; Inosine Monophosphate; Mice; Mice, Knockout; Muscle Contraction; Muscle Fibers, Skeletal; Muscle Weakness; Muscle, Skeletal; Phosphocreatine; Stress, Mechanical

To investigate the metabolic and functional status of muscles of fibromyalgia (FM) patients, using P-31 magnetic resonance spectroscopy (MRS).. Twelve patients with FM and 11 healthy subjects were studied. Clinical status was assessed by questionnaire. Biochemical status of muscle was evaluated with P-31 MRS by determining concentrations of inorganic phosphate (Pi), phosphocreatine (PCr), ATP, and phosphodiesters during rest and exercise. Functional status was evaluated from the PCr/Pi ratio, phosphorylation potential (PP), and total oxidative capacity (Vmax).. Patients with FM reported greater difficulty in performing activities of daily living as well as increased pain, fatigue, and weakness compared with controls. MRS measurements showed that patients had significantly lower than normal PCr and ATP levels (P < 0.004) and PCr/Pi ratios (P < 0.04) in the quadriceps muscles during rest. Values for PP and Vmax also were significantly reduced during rest and exercise.. P-31 MRS provides objective evidence for metabolic abnormalities consistent with weakness and fatigue in patients with FM. Noninvasive P-31 MRS may be useful in assessing clinical status and evaluating the effectiveness of treatment regimens in FM.

Topics: Adenosine Triphosphate; Adult; Fatigue; Female; Fibromyalgia; Health Status; Humans; Magnetic Resonance Spectroscopy; Male; Middle Aged; Muscle Weakness; Muscle, Skeletal; Pain; Phosphates; Phosphocreatine; Phosphorus; Physical Exertion; Self-Assessment; Thigh