and it can severely reduce a patient’s quality of life. It consumes approximately 2% of the National Health Service budget in the United Kingdom, and in the United States, the total annual cost of treatment for heart failure is approximately $28 billion. Moreover, the financial burden of heart failure will increase in coming decades because of the aging population and the improved treatments of its causes. Over the past 20 years, there has been considerable progress in the treatment of chronic heart failure with angiotensin-converting–enzyme (ACE) inhibitors, 4,5 aldosterone antagonists, 6 beta-receptor blockers, 7,8 and resynchronization therapy. 9,10 Even with the very best of modern therapy, however, heart failure is still associated with an annual mortality rate of 10%. 10 The search for better treatments is one of the major challenges in cardiology. Chronic heart failure is multifactorial. There are many reasons why a human heart can fail, 11 but the available evidence suggests that the failing heart is an engine out of fuel — that is, altered energetics play an important role in the mechanisms of heart failure. For this reason, the modulation of cardiac metabolism has promise as a new approach to the treatment of heart failure. This review describes cardiac energy metabolism, appraises the methods used for its assessment, evaluates the role of impaired energy metabolism in heart failure, and gives options for metabolic therapy.

/pdf/the-failing-heart-an-engine-out-of-fuel-3m3ohmvi7b.pdf

The failing heart--an engine out of fuel.

Fatigue, defined as the failure to maintain the required or expected power output, is a complex problem, since multiple factors are clearly involved, with the relative importance of each dependent on the fiber type composition of the contracting muscles(s), and the intensity, type, and duration of the contractile activity. The primary sites of fatigue appear to be within the muscle cell itself and for the most part do not involve the central nervous system or the neuromuscular junction. The major hypotheses of fatigue center on disturbances in the surface membrane, E-C coupling, or metabolic events. The cell sites most frequently linked to the etiology of skeletal muscle fatigue are shown in Figure 1. Skeletal muscles are composed of at least four distinct fiber types (3 fast twitch and 1 slow twitch), with the slow type I and fast type IIa fibers containing the highest mitochondrial content and fatigue resistance. Despite fiber type differences in the degree of fatigability, the contractile properties undergo characteristic changes with the development of fatigue that can be observed in whole muscles, single motor units, and single fibers. The Po declines, and the contraction and relaxation times are prolonged. Additionally, there is a decrease in the peak rate of tension development and decline and a reduced Vo. Changes in Vo are more resistant to fatigue than Po and are not observed until Po has declined by at least 10% of its initial prefatigued value. However, the reduced peak power by which fatigue is defined results from both a reduction in Vo and Po. In the absence of muscle fiber damage, the prolonged relaxation time associated with fatigue causes the force-frequency curve to shift to the left, such that peak tensions are obtained at lower frequencies of stimulation. In a mechanism not clearly understood, the central nervous system senses this condition and reduces the alpha-motor nerve activation frequency as fatigue develops. In some cases, selective LFF develops that displaces the force-frequency curve to the right. Although not proven, it appears likely that this condition is associated with and likely caused by muscle injury, such that the SR releases less Ca2+ at low frequencies of activation. Alternatively, LFF could result from a reduced membrane excitability, such that the sarcolemma action potential frequency is considerably less than the stimulation frequency.(ABSTRACT TRUNCATED AT 400 WORDS)

Cellular mechanisms of muscle fatigue

Review of the Folin phenol protein quantitation method of Lowry, Rosebrough, Farr and Randall.

1. The present study was undertaken to test whether creatine given as a supplement to normal subjects was absorbed, and if continued resulted in an increase in the total creatine pool in muscle. An additional effect of exercise upon uptake into muscle was also investigated. 2. Low doses (1g of creatine monohydrate or less in water) produced only a modest rise in the plasma creatine concentration, whereas 5g resulted in a mean peak after 1h of 795 (SD 104) mumol/l in three subjects weighing 76-87 kg. Repeated dosing with 5g every 2h sustained the plasma concentration at around 1000 mumol/l. A single 5g dose corresponds to the creatine content of 1.1 kg of fresh, uncooked steak. 3. Supplementation with 5g of creatine monohydrate, four or six times a day for 2 or more days resulted in a significant increase in the total creatine content of the quadriceps femoris muscle measured in 17 subjects. This was greatest in subjects with a low initial total creatine content and the effect was to raise the content in these subjects closer to the upper limit of the normal range. In some the increase was as much as 50%. 4. Uptake into muscle was greatest during the first 2 days of supplementation accounting for 32% of the dose administered in three subjects receiving 6 x 5g of creatine monohydrate/day. In these subjects renal excretion was 40, 61 and 68% of the creatine dose over the first 3 days. Approximately 20% or more of the creatine taken up was measured as phosphocreatine. No changes were apparent in the muscle ATP content.(ABSTRACT TRUNCATED AT 250 WORDS)

Elevation of creatine in resting and exercised muscle of normal subjects by creatine supplementation

Benjamin A. Lipsky, Anthony R. Berendt, H. Gunner Deery, John M. Embil, Warren S. Joseph, Adolf W. Karchmer, Jack L. LeFrock, Daniel P. Lew, Jon T. Mader, Carl Norden, and James S. Tan Medical Service, Veterans Affairs Puget Sound Health Care System, and Division of General Internal Medicine, Department of Medicine, University of Washington School of Medicine, Seattle, Washington; Bone Infection Unit, Nuffield Orthopaedic Centre, Oxford, United Kingdom; Northern Michigan Infectious Diseases, Petoskey, Michigan; Section of Infectious Diseases, Department of Medicine, University of Manitoba, Winnipeg, Manitoba; Section of Podiatry, Department of Primary Care, Veterans Affairs Medical Center, Coatesville, Pennsylvania; Division of Infectious Diseases, Department of Medicine, Harvard Medical School, and Beth Israel Deaconess Medical Center, Boston, Massachusetts; Dimensional Dosing Systems, Sarasota, Florida; Department of Medicine, Service of Infectious Diseases, University of Geneva Hospitals, Geneva, Switzerland; Department of Internal Medicine, The Marine Biomedical Institute, and Department of Orthopaedics and Rehabilitation, University of Texas Medical Branch, Galveston, Texas; Department of Medicine, New Jersey School of Medicine and Dentistry, and Cooper Hospital, Camden, New Jersey; and Department of Internal Medicine, Summa Health System, and Northeastern Ohio Universities College of Medicine, Akron, Ohio

/pdf/diagnosis-and-treatment-of-diabetic-foot-infections-1onwvm07xk.pdf

Diagnosis and Treatment of Diabetic Foot Infections

In order to explain the insulin-like effect of exercise, it was proposed in 1951 that contracting muscle fibers liberate creatine, which acts to produce an acceptor effect--later called respiratory control--on the muscle mitochondria. The development of this notion paralleled the controversy between biochemists and physiologists over the delivery of energy for muscle contraction. With the demonstration of functional compartmentation of creatine kinase on the mitochondrion, it became clear that the actual form of energy transport in the muscle fiber is phosphorylcreatine. The finding of an isoenzyme of creatine phosphokinase attached to the M-line region of the myofibril revealed the peripheral receptor for the mitochondrially generated phosphorylcreatine. This established a molecular basis for a phosphorylcreatine-creatine shuttle for energy transport in heart and skeletal muscle and provided an explanation for the inability to demonstrate experimentally a direct relation between muscle activity and the concentrations of adenosine triphosphate and adenosine diphosphate.

https://science.sciencemag.org/content/sci/211/4481/448.full.pdf

Transport of energy in muscle: the phosphorylcreatine shuttle

Protein determination by Lowry's method in the presence of sulfhydryl reagents.

Compartmentation of mitochondrial creatine phosphokinase. I. Direct demonstration of compartmentation with the use of labeled precursors.

Publisher Summary This chapter focuses on two enzymes, hexokinase (HK) and creatine phosphokinase (CPK), and their compartmentation in association with mitochondria. It discusses how hexokinase might be influenced by insulin in the creation or maintenance of a compartment affecting cellular metabolism in a significant way. In the acceptor theory of insulin action, the energy is supplied by enhanced mitochondrial activity. This model is based on the proposition that insulin induces a coupling of hexokinase to an energy-generating site in the mitochondrion. This attachment creates a “compartment” in which the efficiency of two processes, specifically the transfer of adenosine triphosphate (ATP) to hexokinase and the return of adenosine diphosphate (ADP) to the oxidative phosphorylation site, is increased.

Paul J. Geiger

Papers

Transport of energy in muscle: the phosphorylcreatine shuttle

Protein determination by Lowry's method in the presence of sulfhydryl reagents.

Compartmentation of mitochondrial creatine phosphokinase. I. Direct demonstration of compartmentation with the use of labeled precursors.

Compartmentation of Hexokinase and Creatine Phosphokinase, Cellular Regulation, and Insulin Action

Formation of creatine phosphate from creatine and 32P-labelled ATP by isolated rabbit heart mitochondria