Effect of voluntary wheel-running exercise on muscles of the mdx mouse.

The purpose of this study is to determine whether dystrophin-deficient mdx mice are more susceptible to muscle injury and functional impairment than normal C57 mice when allowed to exercise voluntarily on mouse wheels. The mdx mice were significantly impaired when compared to controls as shown by functional, contractile and morphometric responses. The distance young mdx mice ran was 67-78% of young C57 mice, while adult mdx mice ran 31-48% of adult controls. After exercise the slow, oxidative soleus of young and adult mdx mice exhibited hypertrophy with no changes in strength or fatiguability, while the young C57 mice increased strength and the adults became less fatiguable. In the adult mdx mice the fast EDL, which is primarily glycolytic, exhibits slight hypertrophy with a loss of strength, while the young exhibit no changes. These results indicate that the mdx mouse adapts differently than the C57 mouse to even moderate exercise.

The effect of age on the nucleic acid content of slow- and fast-twitch muscle in normal and dystrophic mice and their litter mates.

RNA, DNA, and NCP content were measured in fast- and slow-twitch skeletal muscle of normal and dystrophic mice (HDM) and their littermates at ages 4 through 29 weeks. In normal and litter mate mice RNA and DNA content were far greater in the soleus than in the gastrocnemius while the RNA/DNA ratio and NCP content were greater in the gastrocnemius. In dystrophic mice, however, the differences between nuleic acid content of the 2 muscles were far less, apparently due to a proportionately higher content in the dystrophic gastrocnemius. Due to a proportionately lower ratio in the gastrocnemius, dystrophic RNA/DNA ratios for the 2 muscles were essentially the same. Age had a marked effect on the nucleic acid content of both muscles in all 3 mice types but to varying degrees. In the soleus, RNA and DNA content rapidly decreased until 9 to 10 weeks of age followed by a gradual decline. Soleus RNA/DNA ratios showed little change with age except in the HDM mice in which there was a significant overall decline. In the gastrocnemius, RNA content followed the same pattern but with a smaller decline in the younger ages. Age had no affect on DNA content in the normal gastrocnemius, but there was significant decline in the HDM gastrocnemius. RNA/DNA gastrocnemius ratios showed marked fluctuations in both normal and dystrophic mice but did not appear to be affected by age.

Incidence of acetylcholinesterase in the sarcoplasm of human and chicken muscles.

Fifty-nine biopsies of human muscle, 53 of them abnormal, 6 normal, were studied for the histochemical localization of acetylcholinesterase (AChE) using frozen sections and light microscopy. In addition to AChE which was found at the myoneural and myotendon junction, specific staining was found around the periphery of many fibers from normal and abnormal muscles. Moreover, AChE activity was found to be high in the sarcoplasm of more than 10% of the fibers from 28 biopsies of abnormal muscle including cases of hemiplegia, spinal cord injury, denervation and neuropathy, infantile spinal muscle atrophy, Duchenne, limb-girdle and facioscapulohumeral dystrophies, Schwartz-Jampel syndrome and a myasthenic syndrome. Of the muscles from experimental animals examined, only the Rhesus monkey exhibited AChE around the periphery of the fibers, and only the dystrophic chicken and not the dystrophic mouse or hamster, showed extensive sarcoplasmic AChE. Histograms of muscle fiber diameters indicated that AChE in the sarcoplasm was associated with fibers of all sizes, depending on the nature of the disorder examined. Fibers containing AChE were smaller than unstained fibers in dystrophic chicken muscle. The results suggest that in the human, sarcoplasmic AChE is reversibly repressed during muscle maturation and that its mode of regulation by motor neurons is similar to that found in the chicken.

The role of physiatry in the management of neuromuscular disease.

Patients with neuromuscular disease (NMD) are complex and pose a myriad of clinical problems. Management is best carried out by a team consisting of physicians, physical, occupational, and speech therapists, social workers, vocational counselors, and psychologists, among others. Physiatrists are well-suited to this type of multi-disciplinary care and can play a significant role in the care of these patients.

Rehabilitation research in neuromuscular diseases: current research activities and future research needs.

Rehabilitation management of individuals with neuromuscular disorders has been based primarily on clinical observation. Most investigations of treatment failed to follow sound clinical research techniques and were retrospective. In addition to using appropriate clinical research methodology, 2 parallel categories of research are desirable: investigations of the natural course of each disease, and studies of treatment outcomes. Prospective studies are needed of treatment interventions designed to include an adequate treatment group sample, control subjects matched for duration or severity of disease, supervised therapy sessions, an appropriate objective, valid and reliable measurement criterion against which to assess outcomes, and a double blind system.

Rehabilitation management of muscular dystrophy and related disorders: II. Comprehensive care.

Management of patients with motor unit diseases is now more aggressive than in the past. Most physicians and therapists now believe that it is important to preserve maximal function as long as possible. Treatment should be prospective to inhibit deformity, prolong independent ambulation, and maximize functional capabilities. Management can best be carried out by a multidisciplinary approach to comprehensive care, and should consider the entire needs of the patient. Major goals are early diagnosis and establishment of a rehabilitation plan, maintenance of ADL and ambulation as long as possible, anticipation of complications, and the development of a program of prevention and supportive counseling to patient and family.

Muscle weakness and atrophy-clinical and laboratory evaluation.

A thorough family history, the age at the time of onset and detailed information regarding the rate, mode of progression and distribution of weakness is needed for evaluation of patients with weakness and atrophy. Associated findings such as dermal lesions, tenderness, myotonia and fasciculations should also be noted.The major diagnostically useful laboratory tests are electromyography, nerve conduction, serum enzyme levels and muscle biopsy.Each clinical and laboratory finding should be categorized in terms of its neuro-anatomical origin, since weakness may result from disturbances in the corticospinal pathways, the lower motor neuron, the myoneural junction and the muscle.

Rehabilitation management of muscular dystrophy and related disorders: I. The role of exercise.

When evaluating the effect of a modality such as exercise, maturation in children, the rate of progression of the disease, and the degree of weakness should be considered. The two major factors critical in producing overwork weakness are the degree of weakness at the time the exercise program is started and the intensity of the exercise training program. Exercise therapy is apparently not harmful and may be beneficial in patients with motor unit diseases if it is started early in the course of the diseases when muscle fiber degeneration is minimal, and is carried out at submaximal levels.

Slowly progressive proximal weakness: limb-girdle syndromes.

Many diseases of the motor unit result in slowly progressive limb-girdle weakness. Difficulty in diagnosis arises because many of these disorders share a similar genetic pattern, and some are heterogeneous. Most of the symptoms have such a broad range that they are of limited diagnostic value, and physical findings, even within families, often cover a wide spectrum. With a few exceptions, laboratory data are often of only limited diagnostic assistance. This review documents the need for a careful genetic, clinical, and laboratory evaluation in these disorders, affirms the importance of clinical observation, and identifies the most dependable clinical and laboratory findings.

Fast and slow skeletal muscles: simultaneous in vitro study.

Simultaneous study of the function of fast and slow twitch skeletal muscles in the same in vitro preparation has obvious advantages. Equipment, method and technique are described for study of the soleus (slow) and extensor digitorum longus (fast) muscles from the mouse, and the problems involved in preparing and standardizing these studies are discussed. For nearly maximum function to be obtained from both muscles, careful attention must be given to the stimulus parameters used. Three separate studies were necessary to determine the appropriate stimulus duration, frequency and rest interval between the stimulus trains. The results indicate that for study of tetanic tension and rate of tension development of these muscles from the C57 NAB strain of mice at 20C the most satisfactory stimulus parameters are : duration 2 msec, frequency 100 pulses per second and duration of the stimulus train 700 msec. Rest interval between stimulus trains was two minutes as problems developed with rest intervals less than two minutes or greater than four minutes.

Serial manual muscle testing in Duchenne muscular dystrophy.

Serial measurements of muscle strength of 34 muscle groups were obtained for up to a seven-year period using manual muscle testing (MMT) in a group of 63 boys (mean age = 11.5 years) with Duchenne muscular dystrophy (DMD) not using lower extremity bracing or corrective surgery for ambulation, in order to define the natural course of strength loss and its relation to anthropometric variables and ambulatory status. When correlating the first MMT assessment of each patient with age, strength was found to decrease linearly (-0.26 +/- 0.30 MMT units/year) with time until approximately age 14 when a marked decrease in progression was noted (-0.06 +/- 0.03 MMT units/year). Analyzing individual patients longitudinally yielded a similar rate of strength loss. The average muscle score was 3.0 MMT units at the point of full-time wheelchair use. The marked decline in MMT deterioration around age 14 may be an important consideration when assessing the efficacy of therapeutic interventions in adolescent boys with DMD.

Exercise effect on contractile properties of skeletal muscle in mouse muscular dystrophy.

The purpose of this study was to determine the effect of a high repetitive exercise program, treadmill running, on the tetanic tension and rate of tension development of the slow twitch soleus muscle of normal plus dystrophic mice and their littermates. The exercise program used would be considered to be of mild intensity since it failed to produce any detectable histochemical or biochemical changes. In the noninvolved normal and littermate mice, there was no difference in maximum tetanic tension between the exercised and nonexercised control groups. In the normal mice (eight weeks of age), there was a significant decrease in rate of tension development for those exercised for five weeks compared to nonexercised controls. In littermate mice (seven weeks old) exercised for a four-week period, there was also a significantly lower rate of tension development compared to their nonexercised controls. In dystrophic mice (seven weeks old) exercised for only one to two weeks, there was significantly lower tension as well as rate of tension developed for the exercised mice when compared to nonexercised dystrophic mice. In dystrophic mice (six weeks old) exercised for one to two weeks, there was no difference in tension or rate of tension development when compared to nonexercised controls. In both six and seven-week-old littermate mice, also exercised for one to two weeks, this reduction in tension and rate of tension development did not occur. The average life span for the dystrophic mice used in this study is about 30 weeks. Of the nine exercised dystrophic mice scheduled for study at eight weeks, only one survived, suggesting that even the mild exercise used might have shortened their life expectancy.

Contractures in neuromuscular disease.

The percentage of subjects with contractures, mean maximal loss of range, and relative contracture indices are reported in 230 patients, with 11 diseases seen in a neuromuscular disease clinic during a five-year period. The highest percentage of contractures occurred in patients with Duchenne muscular dystrophy. The number of contractures was significantly greater (p less than .001) (1) in the lower than in the upper extremities; (2) in diseases considered myopathic than in those considered neuropathic; (3) in diseases that are X-linked than in those that are not; and (4) in rapidly progressive than in slowly progressive diseases.

Scheuermann's kyphoscoliosis associated with Charcot-Marie-Tooth syndrome.

Much confusion and disagreement exists regarding the classification and characteristics of inherited disorders manifesting neurogenic muscular atrophy. Many authors consider Charcot-Marie-Tooth syndrome (CMTS) and Roussy Levy syndrome (RLS) forme fruste or variants of Friedreich's ataxia (FA). Familial kyphoscoliosis has often been described in FA and RLS but not with CMTS. The purpose of this paper is to present detailed clinical and laboratory findings in a family with three cases of Scheuermann's kyphoscoliosis and CMTS in three generations. In all cases Scheuermann's kyphoscoliosis was associated with pes cavus, markedly diminished vibratory and position sensation in the lower extremities, absent deep tendon reflexes and muscular atrophy, predominantly of the distal muscles. Fine rhythmic tremor of outstretched hands and positive Romberg sign were present in one case only. Serum creating phosphokinase was elevated in two cases. Motor nerve conduction studies revealed impaired function in the median, ulnar, tibial and peroneal nerves. Sensory nerve conduction wal also impaired in median and ulnar nerves. There was evidence of left ventricular hypertrophy in one case only. The nosology and relationship between CMTS, RLS and FA are discussed.

Relationship of manual muscle testing to objective strength measurements.

This study investigates the relationship between manual muscle test scores (MMT) and quantitative isometric strength measurements (QIS). It also evaluates the implications of that relationship for design of therapeutic trials. Extension and flexion strength at the elbows, hips, and knees of 21 neuromuscular disease patients were tested a total of 26 times utilizing both MMT and QIS testing. Paired data were evaluated with Spearman ranked correlation coefficients, and then QIS was predicted from MMT using Lowess, a consistent form of nonparametric regression. Finally, the implications of the Lowess analysis for designing a therapeutic trial were evaluated. MMT and QIS measurements were significantly correlated in all movements tested. Lowess analysis yielded prediction errors ranging from 16 to 24% of QIS range. Analysis of the sample size needed for a therapeutic trial suggested that a protocol measuring MMT would require more subjects for the same level of statistical significance as a protocol measuring QIS. Since it was not possible to reliably predict QIS values from MMT scores, such conversions are not appropriate for clinical use. This inconsistent relationship between MMT and QIS carries major implications for the design of therapeutic trials. Since therapeutic trials are time consuming, expensive, and most centers do not have large numbers of individuals available, using QIS as an outcome measure is a preferable research design.

Upper vs lower extremity functional loss in neuromuscular disease.

Functional rating scales have been developed for evaluation of upper extremity (UE) and lower extremity (LE) function in Duchenne muscular dystrophy (DMD). The Vignos scale is accepted for LE function and the Brooke scale for UE evaluation. The assumption that UE functional loss parallels LE loss has never been tested. Furthermore, there are no studies examining the relationship between UE/LE strength. This study tests the hypothesis that UE/LE strength and functional losses are parallel in DMD and other neuromuscular disorders. Vignos grades, Brooke grades, and manual muscle test scores were determined for 27 patients with DMD, 10 patients with fascioscapulohumeral muscular dystrophy (FSH), 24 patients with myotonic muscular dystrophy (MMD) and 29 patients with other (Becker's dystrophy and limb-girdle syndrome) proximal myopathies (PM). Spearman correlation coefficients were calculated for UE vs LE functional grade and strength scores and subjected to significance analysis. While all correlations were statistically significantly different from zero (p less than 0.01), all were also significantly different from one (p less than 0.01), none representing perfect equivalence. Coefficients of determination indicated that a maximum of 86% (FSH) of variation in UE rank could be explained purely by observing LE rank. While there is a significant relationship between UE/LE strength and functional grade, these measurements were not found to be entirely equivalent. Therefore, while measures of lower body function or strength might be used as a substitute for UE measurements in drug trials in which global effects are expected, the two measurements are not equivalent when evaluating an individual's clinical status.

Functional ability and equipment use among patients with neuromuscular disease.

The relationship between graded functional ability of a neuromuscular disease patient and his routine daily activities remains unknown. Mobility equipment use may provide an indirect measure of routine daily activities. In this study 110 neuromuscular disease patients were evaluated for both functional grade (Brooke upper extremity and Vignos lower extremity scales) and equipment use. Although several of the Vignos and Brooke categories did not describe significant numbers of these patients, the Vignos scale was able to predict whether or not a given patient would use a wheelchair with 94% accuracy, while the Brooke scale was only 85% accurate. It was not possible to predict manual vs electric wheelchair use based on functional rating scores. Patients with proximal weakness, regardless of diagnosis, displayed a similar pattern of functional outcome and equipment use, which was significantly different from the pattern displayed by groups with distal weakness. As expected, as functional ability diminished, wheelchair use increased; however, wheelchair use began at surprisingly high functional levels. Patients generally preferred a combination of manual and electric wheelchair use.

Upper extremity functional rating for patients with Duchenne muscular dystrophy.

The corresponding deterioration of upper extremity strength and functional capability with increasing age and the relationship between average strength and function were evaluated in 28 boys with Duchenne muscular dystrophy (DMD). Manual muscle testing (MMT) was used to evaluate strength and the Brooke upper extremity grading scale to rate upper extremity function. Mean MMT was found to relate to age in logarithmic fastion, ie, a 1% increase in age led to a 0.9% decrease in mean MMT. Functional grade (FG) related to age in a more complex fashion, revealing three groups based on age: under age 10, all in FG 1; between ages 10 and 13, concentration in FG 2 through 4; and over age 13, eight of ten in FG 5. Regression analysis did not contribute further useful information. Finally, mean MMT was found to be highly significantly related to FG. The plot of mean MMT against FG revealed an S-shaped curve, with rapidly rising functional grade once an average upper extremity strength of 4w was reached. The Brooke scale appears to be useful in describing upper extremity function among DMD patients, although it may reflect a three-grade rather than a six-grade discrimination capability. In describing the natural history of DMD, this scale demonstrates a pattern of rapid functional deterioration during the early adolescent years. This functional deterioration apparently takes place when the decline in strength reaches a threshold which cannot be compensated by muscle substitutions. At that time function deteriorates along a relatively rapid but undefined course.