Forearm 3-methylhistidine efflux in myotonic dystrophy.

Myotonic dystrophy is associated with progressive muscular atrophy. To define the mechanism of muscle wasting in this disease, we studied myofibrillar proteolysis in vivo in 8 men moderately affected with myotonic dystrophy, and compared the results with those of 10 normal men. Myofibrillar proteolysis was estimated by measuring the 3-methylhistidine arteriovenous difference (A-V) and efflux (Q) across the forearm in the postabsorptive state. Plasma 3-methylhistidine concentrations were determined by high-performance liquid chromatography with postcolumn o-phthalaldehyde derivatization and fluorescence detection. Plasma flow to the forearm muscles (F) was estimated to represent 85% of total forearm plasma flow as determined by the indicator-dilution technique. Forearm 3-methylhistidine efflux was calculated as: Q = F(A-V). Mean muscle mass (24-hour creatinine excretion), lean body mass, and forearm volume were decreased in the patients with myotonic dystrophy, confirming the presence of muscle atrophy. Mean forearm 3-methylhistidine arteriovenous difference and efflux were not significantly different in the two groups. We conclude that myofibrillar protein degradation is not increased in myotonic dystrophy, even when measured in a muscle compartment selectively affected by wasting. Muscle atrophy in myotonic dystrophy is probably the result of defective anabolism rather than accelerated catabolism.

Left ventricular thrombus and systemic emboli complicating the cardiomyopathy of Duchenne's muscular dystrophy.

A 17-year-old boy with Duchenne's muscular dystrophy and congestive cardiomyopathy with a left ventricular thrombus is described. The patient presented with flank pain, and computed tomography of the abdomen revealed multiple bilateral renal infarcts. An echocardiogram delineated a left ventricular thrombus and generalized hypokinesis with a left ventricular ejection fraction of 25%. Heparin therapy was started, but the patient died of refractory congestive heart failure. Autopsy revealed diffuse skeletal myopathy consistent with Duchenne's muscular dystrophy as well as biventricular cardiomyopathy with a recent left ventricular apical-septal mural thrombus. Right atrial thrombus, a left upper lobe pulmonary embolus, and splenic and renal infarcts were also noted. To our knowledge, this is the first reported case of left ventricular thrombus with or without systemic emboli in the cardiomyopathy of Duchenne's muscular dystrophy.

Phenytoin-induced improvement in muscle cramping and insulin action in three patients with the syndrome of insulin resistance, acanthosis nigricans, and acral hypertrophy.

Phenytoin sodium has been used to treat muscle cramps of diverse causes, and is known to increase insulin sensitivity during long-term use. We have previously described a syndrome of insulin resistance, acanthosis nigricans, and acral hypertrophy with continual muscle cramping. The effect of 300 mg/d of phenytoin (Dilantin) on muscle cramping and carbohydrate economy was studied in three affected patients and four control subjects. Oral glucose tolerance tests, euglycemic insulin infusion studies, and monocyte insulin binding tests were conducted before and after phenytoin administration. All three patients had notable improvement in muscle cramps. In response to phenytoin, metabolic improvements were variable, with improvement characteristically better in patients with less severe baseline metabolic abnormalities. Patient 1, with the mildest degree of glucose intolerance, had decreased fasting insulin and blood glucose levels, improved glucose tolerance, and insulin-mediated glucose disposal, associated with an increase in monocyte insulin receptors. Patient 2 had reduced fasting plasma glucose and insulin levels and improved oral glucose tolerance, suggesting a beneficial effect on carbohydrate metabolism. Patient 3, with the most severely impaired carbohydrate economy, showed no metabolic improvement despite marked lessening of muscle pain. These clinical characteristics were unaffected in control subjects. We conclude that phenytoin is of value in the therapy of muscle cramps and glucose intolerance in patients with this syndrome.

Potassium uptake in muscle during paramyotonic weakness.

Previous studies have suggested that an abnormal release of potassium from muscle may accompany attacks of paramyotonic weakness. We investigated 3 patients with paramyotonia congenita before and after the induction of forearm muscle weakness by exercise in cold water. Two of these patients had paralysis periodica paramyotonica and the 3rd had paramyotonia congenita. At the time of paramyotonic weakness there was a marked increase in the arterialized-venous concentration difference of potassium across forearm muscle. This indicated a significant uptake of potassium by forearm muscle in all 3 patients. Normal controls showed a slight release of potassium both at rest and after exercise in cold water. These results suggest that (1) the sodium-potassium pump of the muscle fiber is operating efficiently during paramyotonic weakness; and (2) there is a different mechanism responsible for the generalized weakness that occurs in hyperkalemic periodic paralysis.

Treatment of muscular dystrophies.

1. Specific therapies to cure the muscular dystrophies are not yet available. Therapeutic trials designed on the basis of our understanding of the pathophysiology of these disorders have had only limited success. 2. However, recent investigations in Duchenne muscular dystrophy have identified the abnormal gene and the missing or defective gene product, dystrophin. 3. These discoveries provide information which will lead to more rational and specific therapeutic approaches. 4. The advances in genetic research have led to more effective preventive therapy. Gene mapping has been applied successfully in carrier detection and antenatal diagnosis, and specific gene probes will soon become available for carrier testing for the two most common forms of muscular dystrophy, Duchenne muscular dystrophy and myotonic dystrophy. 5. Supportive therapies for muscular dystrophy patients now include respiratory support for selected patients with chronic respiratory insufficiency. 6. This review will focus on the two most common muscular dystrophies, Duchenne muscular dystrophy and myotonic dystrophy.

Inflammatory myopathies.

The inflammatory myopathies are a heterogeneous group of disorders with recent evidence demonstrating differences in clinical features, pathologic changes, pathogenesis, and response to therapy. The inflammatory myopathies generally produce predominantly proximal, symmetric muscle weakness and wasting. Additional criteria for diagnosis include elevated serum muscle enzymes, myopathic features on EMG, and muscle biopsy abnormalities, including muscle fiber necrosis, degeneration, and inflammatory infiltrates. Inclusion body myositis is distinctive in that distal weakness is most commonly equal to or greater than proximal weakness and muscle biopsy reveals rimmed, cytoplasmic vacuoles, eosinophilic inclusions in the cytoplasm, and nucleus and abnormal filamentous structures. Autoimmune mechanisms seem likely to be involved in the pathogenesis of these disorders and viral infection may be etiologically involved in some of these diseases. The differences in the site of immune-mediated damages suggest an angiography in dermatomyositis while direct muscle fiber involvement is more likely in polymyositis and inclusion body myositis. Therapy of these disorders is similar although some, particularly inclusion body myositis, may be particularly resistant to therapy. Prednisone is currently recommended as the first treatment with azathioprine or methotrexate added after 3 months if steroids are ineffective.

Lack of rapid enhancement of insulin action after oral glucose challenge in myotonic dystrophy.

Oral glucose administration to normal humans stimulates insulin release and simultaneously enhances the action of insulin by producing a rapid increase in tissue insulin sensitivity by a mechanism separate from the amount of hormone released. We determined whether insulin-resistant patients with myotonic dystrophy lose the ability to produce the normal rapid increase in tissue insulin action after oral glucose. Nine ambulatory, nonobese men with myotonic dystrophy were studied with 120-min euglycemic insulin infusions (20 mU X m-2 X min-1) given before and after glucose ingestion (4 and 5 patients received 15- and 25-g loads, respectively). Identical studies were performed in nonobese normal volunteers (16 and 13 patients received 15- and 25-g oral glucose loads, respectively). Glucose infusion rates at 20-120 min (GIR20-120) during euglycemic insulin infusions without prior glucose were 2.87 +/- 0.6 mg X kg-1 X min-1 in patients with myotonic dystrophy compared to 4.70 +/- 0.3 mg X kg-1 X min-1 in normal subjects. Euglycemic insulin infusions after glucose ingestion were begun after arterialized blood glucose values had returned to baseline. After glucose ingestion by normal subjects, GIR20-120 increased by 44.4 +/- 7.1% (P less than .0001) and by 46.8 +/- 8.6% (P less than .0002) with 15- and 25-g glucose loads, respectively. GIR20-120 in the nine patients with myotonic dystrophy showed no significant increase after glucose ingestion. These results confirmed the existence of a decrease in whole-body insulin sensitivity in myotonic dystrophy and indicated that the patients lack the normal mechanism that enhances insulin action after oral glucose.(ABSTRACT TRUNCATED AT 250 WORDS)

Basal metabolic rate in myotonic dystrophy: evidence against hypometabolism.

We studied the basal metabolic rate in 13 males with myotonic dystrophy and 14 normal male subjects. Basal O2 consumption (VO2) and CO2 production (VCO2) were measured by direct gas analysis with a ventilated hood system. Lean body mass was estimated by total body potassium (40K method) and muscle mass by urine creatinine excretion. The basal metabolic rate of patients with myotonic dystrophy was significantly reduced when related to surface area (-9%), but elevated when related to lean body mass (+17%). Previous reports of hypometabolism in myotonic dystrophy did not take into account the amount of muscle wasting in this disorder, and we conclude that in myotonic dystrophy the basal metabolic rate is actually elevated when corrected for lean body mass.

Effect of testosterone on whole body amino acid utilization in myotonic dystrophy.

Patients with myotonic dystrophy are markedly insulin resistant and have an associated abnormality in the regulation of arterialized amino acid concentrations during euglycemic insulin infusions. We studied the effect of testosterone treatment on whole body amino acid balance in myotonic dystrophy, since it increases muscle mass and muscle protein synthesis rate. Six patients with myotonic dystrophy underwent studies of glucose disposal and amino acid regulation during low dose insulin infusions with maintenance of euglycemia, prior to and after 10 to 13 weeks of testosterone (3 mg/kg/wk). Testosterone increased the insulin-stimulated decline of certain amino acids, but did not improve whole body glucose uptake. The anabolic effect of testosterone is separate from the anabolic effect of insulin.

Insulin resistance and regulation of serum amino acid levels in myotonic dystrophy.

To quantify the degree of whole body insulin resistance in patients with myotonic dystrophy and to determine if these same patients display signs of a whole body decrease in the action of insulin on amino acid uptake and glucose disposal, three separate 120 min studies employing the euglycaemic insulin clamp technique (20, 80 and 200 m-units min-1 m-2) were performed on five ambulatory patients with myotonic dystrophy. The results were compared with findings obtained in identical studies in 21 normal volunteers. Myotonic dystrophy patients showed a slower, less marked decline in the serum concentration of insulin sensitive amino acids (threonine, valine, leucine, isoleucine, tyrosine, phenylalanine) during all three insulin infusions compared with normals. The greatest difference occurred at the low physiological elevations of insulin produced by the 20 m-units min-1 m-2 infusion. Alanine levels fell significantly below baseline in patients with myotonic dystrophy after 60 and 120 min of insulin infusion with all three rates of insulin infusion. Normal subjects had only a minimal, insignificant decline in arterialized alanine concentrations during the three different insulin infusions. Creatinine adjusted rates of whole body glucose disposal were 30-40% lower in the myotonic dystrophy group at all three doses of insulin compared with the normals. This demonstrates that their insulin resistance was not due simply to a reduction in muscle mass. The overall pattern of findings in these studies of patients with myotonic dystrophy indicates that there is a whole body derangement in the regulation of circulating amino acid levels by insulin as well as a marked decrease in the action of this hormone in stimulating glucose uptake by target tissues.

Enhancement of insulin action after oral glucose ingestion.

Previous investigations in normal humans and rats have shown an increase in insulin sensitivity and binding affinity of adipocytes isolated 1-3 h after glucose ingestion. To determine whether a rapid enhancement of the action of insulin follows glucose ingestion in vivo, the present studies have utilized 120-min 20 mU/m2 X min euglycemic insulin infusions before and after 7.5-, 15-, 25-, and 100-g oral glucose loads. Euglycemic insulin infusions after the carbohydrate challenge were begun after arterialized blood glucose and insulin values had returned to baseline. After 15- and 25-g oral glucose loads during the 20-120-min interval of insulin infusion, glucose infusion rates increased by 44 +/- 6% (P less than 0.0001) and 47 +/- 9% (P less than 0.0002), respectively. No significant differences in arterialized glucose or insulin values existed between basal and post-glucose insulin infusions. In addition, no significant differences in hepatic glucose production or counter-regulatory hormone levels were found between basal and post-glucose insulin infusions. Control infusion studies including subjects who ingested saline or mannitol failed to show an increase in insulin action. Studies were carried out to mimic the insulin curve seen after 15- and 25-g oral glucose loads. Euglycemic insulin infusions after these insulin simulation studies show a 34 +/- 7% enhancement compared to baseline euglycemic insulin infusions. These results demonstrate a rapid enhancement of insulin action after oral glucose challenge in normal humans. The insulin simulation studies suggest that insulin itself either directly or through release of another factor acts on muscle to increase insulin sensitivity. The increase in insulin action demonstrated in these investigations may represent an important regulatory mechanism to modulate tissue insulin sensitivity.

The heart in Friedreich's ataxia. Report of a case.

Cardiac abnormalities are a characteristic feature of the autosomal, recessively inherited, spinocerebellar degeneration known as Friedreich's ataxia. We report the pathologic changes in the heart of a 27-year-old woman with Friedreich's ataxia, including ventricular subendocardial fibroelastosis, occlusion of the coronary sinus ostium, individual myofiber loss, myofiber disarray, and markedly enlarged, hyperchromatic myofiber nuclei. A common pathogenetic mechanism may underlie both cardiac and neurological abnormalities.

Intravenous glucose infusion fails to alter monocyte insulin-binding affinity in normal subjects.

Previous investigations have demonstrated an increase in monocyte insulin receptor affinity two and five hours following oral carbohydrate loading. The present studies were undertaken to see if intravenous (IV) glucose challenge provokes a similar increase in monocyte insulin binding affinity. 25 grams of glucose were given to 10 lean normals and monocytes were isolated for 125I-insulin tracer binding studies (8.4 X 10(-10) M) at 0, 1 and 5 hours after glucose loading. The mean data show that monocytes develop a small, statistically insignificant increase in insulin-binding affinity one hour after intravenous glucose (mean +/- SEM, 7.28 +/- 1.06 ng/ml compared to basal 50% insulin displacement value, B50, of 9.25 +/- 1.62 ng/ml). B50 values demonstrated no increase in binding affinity at five hours (10.77 +/- 2.22 ng/ml). Prior studies have shown a 50 to 70% decrease in B50 following oral glucose, indicating a rapid increase in receptor binding affinity after carbohydrate ingestion. In contrast the present studies have shown that after IV glucose six normals had no decrease in B50 at one or five hours, while the remaining four normals had a 35% decrease at one hour but no decrease at five hours. Intravenous glucose loading, unlike an oral carbohydrate challenge, fails to provoke an acute, consistent increase in monocyte insulin binding affinity at these time points. Elevations in plasma glucose and insulin do not by themselves induce the acute increase in receptor affinity.

Rapid increase in the insulin sensitivity of rat adipocytes after intravenous glucose administration.

To study the mechanism underlying the enhancement of insulin action after carbohydrate challenge, rats were given an iv infusion of 100 mg glucose or saline. Adipocytes were isolated 1, 2, and 3 h after the infusions, and their ability to respond to insulin was examined. Two and 3 h postglucose, the cells showed a 50% increase in insulin sensitivity, as measured by glucose incorporation into total lipid and 2-deoxyglucose uptake. The effect was characterized by a leftward shift in the insulin dose-response curve. There was no change in maximum insulin stimulation. Insulin binding by the fat cells and by liver plasma membranes was not altered by glucose administration. These results demonstrate the presence of a physiological process that acutely enhances the insulin sensitivity of rat adipocytes after iv glucose infusion.