Khema R. Sharma

Myoblast implantation in Duchenne muscular dystrophy: The San Francisco study

We evaluated myoblast implantation in 10 boys with Duchenne muscular dystrophy (DMD) and absent dystrophin (age 5–10 years) who were implanted with 100 million myoblasts in the anterior tibial muscle of one leg and placebo in the other. Cyclosporine (5 mg/kg/day) was administered for 7 months. Pre‐ and postimplantation (after 1 and 6 months) muscle biopsies were analyzed. Force generation (tetanic tension and maximum voluntary contraction) was measured monthly in a double‐blind design. There was increased force generation in both legs of all boys, probably due to cyclosporine. Using the polymerase chain reaction, evidence of myoblast survival and dystrophin mRNA expression was obtained in 3 patients after 1 month and in 1 patient after 6 months. These studies suggest a salutary effect of cyclosporine upon muscular force generation in Duchenne muscular dystrophy; however, myoblast implantation was not effective in replacing clinically significant amounts of dystrophin in DMD muscle.

Central basis of muscle fatigue in chronic fatigue syndrome

We studied whether muscle fatigue, metabolism, or activation are abnormal in the chronic fatigue syndrome (CFS). Subjects performed both an intermittent submaximal and a sustained maximal voluntary isometric exercise protocol of the tibialis anterior muscle. The extent of fatigue, metabolic response, and changes in both M-wave amplitude and twitch tension during exercise were similar in patients and controls. The response to systemic exercise was also normal in the patients. However, voluntary activation of the tibialis was significantly lower in the patients during maximal sustained exercise. The results indicate that patients with CFS have (1) normal fatigability and metabolism at both the intracellular and systemic levels, (2) normal muscle membrane function and excitation-contraction coupling, and (3) an inability to fully activate skeletal muscle during intense, sustained exercise. This failure of activation was well in excess of that found in controls, suggesting an important central component of muscle fatigue in CFS.

Physiology of fatigue in amyotrophic lateral sclerosis

Article abstract-We investigated the mechanisms of muscle fatigue in ALS. In the muscles of ALS patients and healthy control subjects, we examined (1) fatigue using measurements of muscle force, (2) energy metabolism using phosphorus-31 magnetic resonance spectroscopy, and (3) activation using neurophysiologic measures and MRI. During 25 minutes of intermittent isometric exercise of the tibialis anterior muscle, both maximum voluntary and tetanic force declined more in patients than in controls, indicating greater fatigability in ALS. There was a similar decline of voluntary and tetanic force, suggesting that much of the fatigue was not central. Evoked compound muscle action potential amplitudes were preserved during exercise in both groups, indicating no failure of neuromuscular transmission; this result suggests that the source of fatigue was not at the neuromuscular junction or within the muscle membrane. In spite of greater fatigability, changes during exercise in energy metabolites and proton signal intensity tended to be less in ALS patients compared with controls, suggesting impaired muscular activation. We conclude that the greater muscle fatigue in ALS patients results from activation impairment, due in part to alterations distal to the muscle membrane. NEUROLOGY 1995;45: 733-740

Cyclosporine increases muscular force generation in Duhenne muscular dystrophy

We investigated the effect of cyclosporine (CsA) on force generation in 15 boys with Duchenne muscular dystrophy (DMD) by obtaining monthly measures of tetanic force and maximum voluntary contraction (MVC) of both anterior tibial muscles. During 4 months of a natural history phase, both tetanic force and MVC declined significantly. During 8 weeks of CsA treatment (5 mg/kg/day), significantly increased tetanic force (25.8 ± 6.6%) and MVC (13.6 ± 4.0%) occurred within 2 weeks. The maximum mean increase during treatment was 35.2 ± 5.9% (tetanic force) and 19.0 ± 4.6% (MVC). Side effects from CsA, gastrointestinal and flu-like symptoms, were transient and self-limiting. Thus, as previously reported with prednisone, CsA increases muscular force generation in the anterior tibial muscles of DMD patients.

Excessive muscular fatigue in the postpoliomyelitis syndrome.

To investigate anterior tibial muscle fatigability and metabolism in postpoliomyelitis syndrome patients and controls, we performed measurements of force and relaxation time, as well as 31P magnetic resonance spectroscopy, during intermittent, low-intensity, isometric, voluntary exercise. Both maximum voluntary contraction and tetanic force declined significantly more during exercise and subsequently recovered less in patients compared with controls, indicating greater fatigue in patients. However, intracellular pH and phosphocreatine were not different in the two groups at rest or during exercise or recovery, suggesting that the greater fatigue of the patients was not due to an excessive change of metabolites. Moreover, the pre-exercise half-relaxation time of the tetanus was significantly prolonged in patients compared with controls, and the decline in tetanic force during exercise was linearly related to the half-relaxation time of tetanus, suggesting impaired calcium kinetics. Taken together, the findings of increased fatigability, delayed recovery, and prolonged half-relaxation time, without differences in metabolites, suggest that the fatigue in postpoliomyelitis syndrome may be due to impaired activation beyond the muscle membrane.

Effects of electrically stimulated exercise training on muscle function in multiple sclerosis

To investigate whether electrically stimulated exercise training might reduce muscle fatigue in persons with multiple sclerosis (MS), the dorsiflexor muscles of six patients were trained (60 min/d, 6d/wk, 8 wks) with electrically stimulated endurance exercise (50 Hz tetanic contractions, 25% duty cycle). There was evidence of transient mus cle injury at the onset of training (reduced tetanic force, elevated ratio of inorganic phosphate/phosphocreatine in the resting muscle). There was no significant effect of the training on mean muscle fatigability. After training, four of six patients had reduced fatigue (i.e., fall in tetanic force) during nine minutes of intermittent tetanic contractions. Two subjects had increased fatigue following training. Training-induced changes in fatigability were linearly associated with changes in (1) pre-exercise twitch con traction time (r2 = 0.70), and (2) the decrease in intracellular pH during exercise (r2 = 0.88), suggesting that altered fatigability after training may be associated with changes in the intrinsic properties of the muscle. These results indicate that elec trically stimulated exercise training may benefit some patients with MS. Care must be taken in the design of the stimulation parameters, and signs of muscle injury should be monitored. Further studies are needed to elucidate the most efficacious means of improving muscle strength and resistance to fatigue using electrical stim ulation in MS. Key Words: Metabolism—Muscle injury—Magnetic resonance spec troscopy—Fatigue.—Contraction—Rehabilitation.