Steven F. Lewis

Exercise intolerance, lactic acidosis, and abnormal cardiopulmonary regulation in exercise associated with adult skeletal muscle cytochrome c oxidase deficiency.

A 27-yr-old woman with lifelong severe exercise intolerance manifested by muscle fatigue, lactic acidosis, and prominent symptoms of dyspnea and tachycardia induced by trivial exercise was found to have a skeletal muscle respiratory chain defect characterized by low levels of reducible cytochromes a + a3 and b in muscle mitochondria and marked deficiency of cytochrome c oxidase (complex IV) as assessed biochemically and immunologically. Investigation of the pathophysiology of the exercise response in the patient revealed low maximal oxygen uptake (1/3 that of normal sedentary women) in cycle exercise and impaired muscle oxygen extraction as indicated by profoundly low maximal systemic arteriovenous oxygen difference (5.8 ml/dl; controls = 15.4 +/- 1.4, mean +/- SD). The increases in cardiac output and ventilation during exercise, normally closely coupled to muscle metabolic rate, were markedly exaggerated (more than two- to threefold normal) relative to oxygen uptake and carbon dioxide production accounting for prominent tachycardia and dyspnea at low workloads. Symptoms in our patient are similar to those reported in other human skeletal muscle respiratory chain defects involving complexes I and III, and the exaggerated circulatory response resembles that seen during experimental inhibition of the mitochondrial respiratory chain. These results suggest that impaired oxidative phosphorylation in working muscle disrupts the normal regulation of cardiac output and ventilation relative to muscle metabolic rate in exercise.

Impairment of sympathetic activation during static exercise in patients with muscle phosphorylase deficiency (McArdle's disease).

Static exercise in normal humans causes reflex increases in muscle sympathetic nerve activity (MSNA) that are closely coupled to the contraction-induced decrease in muscle cell pH, an index of glycogen degradation and glycolytic flux. To determine if sympathetic activation is attenuated when muscle glycogenolysis is blocked due to myophosphorylase deficiency (McArdles disease), an inborn enzymatic defect localized to skeletal muscle, we now have performed microelectrode recordings of MSNA in four patients with McArdles disease during static handgrip contraction. A level of static handgrip that more than doubled MSNA in normal humans had no effect on MSNA and caused an attenuated rise in blood pressure in the patients with myophosphorylase deficiency. In contrast, two nonexercise sympathetic stimuli, Valsalvas maneuver and cold pressor stimulation, evoked comparably large increases in MSNA in patients and normals. The principal new conclusion is that defective glycogen degradation in human skeletal muscle is associated with a specific reflex impairment in sympathetic activation during static exercise.

Glucose-induced exertional fatigue in muscle phosphofructokinase deficiency.

BACKGROUND The exercise capacity of patients with muscle phosphofructokinase deficiency is low and fluctuates from day to day. The basis of this variable exercise tolerance is unknown, but our patients with this disorder report that fatigue of active muscles is more rapid after a high-carbohydrate meal. METHODS AND RESULTS To determine the effect of carbohydrate on exercise performance, we asked four patients with muscle phosphofructokinase deficiency to perform cycle exercise under conditions of differing availability of substrate--i.e., after an overnight fast, and during an infusion of glucose or triglyceride (with 10 U of heparin per kilogram of body weight) after an overnight fast. As compared with fasting and the infusion of triglyceride with heparin, the glucose infusion lowered plasma levels of free fatty acids and ketones, reduced maximal work capacity by 60 to 70 percent, and lowered maximal oxygen consumption by 30 to 40 percent. Glucose also increased the relative intensity of submaximal exercise, as indicated by a higher heart rate at a given workload during exercise. The maximal cardiac output (i.e., oxygen delivery) was not affected by varying substrate availability, but the maximal systemic arteriovenous oxygen difference was significantly lower during glucose infusion (mean +/- SE, 5.5 +/- 0.3 ml per deciliter) than after fasting (7.6 +/- 0.4 ml per deciliter, P less than 0.05) or during the infusion of triglyceride with heparin (8.9 +/- 1.3 ml per deciliter, P less than 0.05). CONCLUSIONS In muscle phosphofructokinase deficiency, the oxidative capacity of muscle and the capacity for aerobic exercise vary according to the availability of blood-borne fuels. We believe that glucose infusion lowers exercise tolerance by inhibiting lipolysis and thus depriving muscle of oxidative substrate (plasma free fatty acids and ketones); this impairs the capacity of working muscle to extract oxygen and lowers maximal oxygen consumption.

Skeletal muscle disorders and associated factors that limit exercise performance.

The study of skeletal muscle disorders is providing potentially important insights into regulatory mechanisms in human exercise and fatigue and information useful for diagnostic and treatment purposes. This review primarily concerned the general metabolic and physiological factors which set upper limits to performance of various types of exercise in patients with a variety of muscle disorders. From the standpoint of exercise performance, skeletal muscle diseases can be classified into three major groups. One group consists of primary disorders of muscle energy metabolism, including defects in muscle carbohydrate and lipid metabolism, disorders of mitochondrial electron transport, and abnormalities of purine nucleotide metabolism. Exercise performance largely reflects the capacity for ATP resynthesis. Oxidative phosphorylation is the dominant quantitative source of energy for ATP resynthesis under most exercise conditions. Consequently, patients with disordered oxidative metabolism (i.e., patients with defects in the availability or utilization of oxidizable substrate, such as those with phosphorylase or PFK deficiency or those with defects in mitochondrial electron transport) typically demonstrate severely impaired exercise performance. Intolerance to sustained exercise and premature fatigability are salient features of muscle oxidative disorders. Maximal oxygen uptake and maximal a-v O2 difference are markedly subnormal related to an attenuated muscle oxygen extraction. Muscle weakness and atrophy are less common. Anaerobic muscle performance is dramatically limited in patients with virtually complete defects of glycogenolysis/glycolysis but appears relatively normal in those with electron transport defects. A second major group of disorders includes patients with decreased muscle mass due to muscle necrosis, atrophy, and replacement of muscle by fat and connective tissue. These disorders are exemplified by the various muscular dystrophies (Duchennes dystrophy, Beckers dystrophy, LG dystrophy, FSH dystrophy, and myotonic dystrophy) in which exercise performance is severely impaired due to muscle wasting and weakness in spite of largely normal pathways for muscle ATP resynthesis. In muscular dystrophy patients, the degree to which maximal oxygen uptake and anaerobic muscle performance are impaired appears to be a function of the severity of muscle weakness and atrophy. A third group of disorders includes patients with impaired activation of muscle contraction or relaxation. These disorders may be considered in two subcategories. In the first, impaired activation or relaxation of contractile activity is due to intrinsic muscle dysfunction (e.g., diseases associated with myotonia or periodic paralysis). In the second subcategory, there is impaired muscle activation due to a primary abnormality in the central nervous system, motor nerves, or neuromuscular junction.(ABSTRACT TRUNCATED AT 400 WORDS)

Hyperkinetic circulation during exercise in neuromuscular disease

Increased oxygen transport by the circulation is normally tightly coupled to increased oxygen uptake (VO2) during exercise; cardiac output (Q) increases 5 to 6 liters for every liter of increased oxygen utilization (ΔQ/ΔVO2=5). We measured cardiac output and oxygen uptake at rest and during bicycle exercise in 7 patients with myalgia without evident muscle disease and 15 patients with myopathies. Resting circulation was normal in all patients, and during exercise the increase in cardiac output relative to oxygen uptake was normal in all myalgia and most myopathy patients. However, in four patients (with dermatomyositis, phosphorylase defisiency, carnitine deficiency, and ocular myopathy with “ragged-red fibers”) exercise cardiac output was excessive and ΔQ/ΔVO2 high, resulting in an abnormally high level of cardiac work for a given level of exercise. This hyperkinetic response may represent aberrant regulation of the circulation by skeletal muscle as a consequence of some myopathies.

Pathophysiology of exercise performance in muscle disease.

Diseases of skeletal muscles (myopathies) produce two major patterns of exercise intolerance. In muscular dystrophies, there is a progressive loss of muscle fibers which results in increasing muscle weakness and reduced VO2max due to the loss of functional muscle mass. In disorders of muscle energy metabolism, muscle bulk and resting strength are preserved, but an imbalance in muscle energy production and utilization in exercise results in exertional muscle pain, cramping, weakness, or fatigue. Isometric exercise is impaired by disorders of anaerobic glycolysis. Dynamic exercise is limited by disorders of oxidative metabolism. Maximal oxygen uptake is low in mitochondrial myopathies which affect pyruvate oxidation and electron transport and in glycolytic disorders which limit the availability of carbohydrate for oxidation during high-intensity exercise. In carnitine palmityl transferase deficiency (under non-fasting conditions) VO2max is normal. Excessive cardiopulmonary responses to exercise occur in some mitochondrial myopathies and in myophosphorylase deficiency and may contribute to exercise intolerance in these diseases.

Abnormal ventilation during exercise in McArdle's syndrome Modulation by substrate availability

We evaluated ventilation during cycle exercise in four men lacking myophosphorylase. In submaximal exercise of similar relative intensity, ventilation was higher relative to oxygen uptake in McArdle patients than in normal men. The exercise ventilatory response returned to normal after glucose infusion, by fasting to increase free fatty acid availability or by combining fasting and submaximal exercise. Excessive ventilation in exercise was potentiated by inhibiting lipolysis with nicotinic acid. The excessive ventilatory effort and resultant respiratory alkalosis may contribute to exercise intolerance.

Clinical disorders of muscle energy metabolism

The disorders of muscle energy metabolism can be classified into degenerative (myopathic) and dynamic syndromes. Four dynamic syndromes are currently recognized: 1) defective carbohydrate utilization, due to block of glycogenolysis or glycolysis; 2) defective lipid utilization, due to deficiency of the mitochondrial translocation of long-chain fatty acids (carnitine palmityltransferase deficiency); 3) lactic acidosis, due to defects of mitochondrial electron transport enzymes and possibly other unidentified defects; and 4) abnormal adenine nucleotide metabolism, exemplified by adenylate deaminase deficiency. The way in which the response to exercise is affected by impaired muscle energy metabolism is dependent on the type of metabolic defect. Defective carbohydrate metabolism severely limits the ability for high-intensity and ischemic exercise. The ability to perform prolonged exercise is markedly impaired in dynamic disorders of lipid metabolism. Other disorders, including those of adenine nucleotide metabolism also may have important implications for our understanding of the metabolic phenomena involved in exercise and recovery.

Neuromuscular diseases as models of cardiovascular regulation during exercise

This article reviews the research performed to date on the cardiovascular responses to exercise in patients with neuromuscular diseases and lesions affecting the transmission of afferent impulses from skeletal muscle. These studies have provided important information about the roles of central command and reflexes from skeletal muscle afferents in circulatory control. Few animal models of neuromuscular diseases are available. Studies of patients with specific defects in skeletal muscle energy metabolism are particularly valuable because the local metabolic state participates in both systemic and local cardiovascular regulation. In patients with certain muscle metabolic defects (e.g., McArdles disease, carnitine deficiency) cardiac output is normal at rest but increases excessively in relation to oxygen uptake during exercise. The excessive increase in cardiac output during exercise can be totally or partially normalized by increasing the availability of substrate to exercising muscle. These studies provide unique insights into the specific metabolic factors which are involved in cardiovascular regulation.

Regular Physical Activity: A ‘Magic Bullet' for the Pandemics of Obesity and Cardiovascular Disease

is projected that, by 2050, approximately 42% will be obese, >60% will be overweight and >30% will have type 2 diabetes [6, 7] . In Europe, obesity rates range from 10 to 27% in men and to up to 38% in women [8] . In the UK, >50% of adults are likely to be significantly overweight by 2050 [9] . In 2011, nearly 10% of Europeans had impaired glucose tolerance, a number which is projected to increase to 15% by 2030 [10] . In addition, despite remarkable improvements in mortality over many decades, cardiovascular disease will remain the leading cause of death in the USA and most developed countries, and is rapidly becoming so worldwide. Nobel Prize winner Paul Ehrlich popularized the notion of a ‘magic bullet’ [11] . He theorized a compound selectively targeting a disease-causing organism and a toxin for the organism deliverable along with the selective therapeutic agent. He reasoned that a ‘magic bullet’ (‘magische Kugel’, his term for an ideal agent) would be created that killed only the targeted organism. In the industrialized world today, the totality of evidence indicates that regular physical activity may have the closest resemblance to a magic bullet. Regular physical activity, such as brisk walking for 20 min each day, can be practiced even by the oldest old and can certainly improve the quality and possibly the quantity of life. PhysiThe epidemic of overweight and obesity may already be the leading avoidable cause of premature death in the USA [1] and it is growing rapidly worldwide. In the last decade, up until 2014, the population of the USA was the fattest in the world and likely the fattest in history [2] . The epidemic of overweight and obesity has now spread to Europe and to other developed countries. In 2008, Europe had the second-highest proportion of overweight or obese people after the Americas, and there is an emerging pandemic already adversely affecting developing countries. Specifically, in China and India, which comprise about 1/3 of the population of the world, obesity and overweight are already relatively common in urban areas. For example, in Beijing, the average BMI is about 24.8, the level seen in the USA in the 1990s [3] . Weight gain, overweight and obesity in middle age all increase the risks of developing cardiovascular disease including coronary heart disease and stroke, and also type 2 diabetes, osteoarthritis and some common and fatal cancers such as colon cancer. At present, in the USA, largely due to obesity, there is an unprecedented epidemic of type 2 diabetes, which increases the risks of cardiovascular disease 2to 3-fold in men and 3to 6-fold in women. Obesity currently affects approximately 35% and overweight >50% of the US population, and 10% have type 2 diabetes [4, 5] . It Received: February 16, 2016 Accepted: February 16, 2016 Published online: April 16, 2016