Hyam Isaacs

Respiratory activities of subsarcolemmal and intermyofibrillar mitochondrial populations isolated from denervated and control rat soleus muscles

Ultraturrax and Nagarse released populations of mitochondria isolated from control and day 21 denervated rat soleus muscle were characterized with respect to their oxidative phosphorylation, ADP translocase and ATPase activities. Both Ultraturrax and Nagarse released mitochondrial populations displayed lower capacities for oxidative phosphorylation; lower ADP translocase activities and higher Mg2+ stimulated ATPase activities than their corresponding controls. For both the denervated and control states, the Nagarse-released mitochondrial populations displayed significantly higher respiratory activities than the Ultraturrax released fractions. The significance of these findings is discussed with regard to the process of mitochondrial respiratory control. In addition the role of mitochondrial dysfunction in denervation muscular atrophy is assessed.

Idiopathic cardiomyopathy and skeletal muscle abnormality

The skeletal muscle of three cases presenting with idiopathic congestive cardiomyopathy has been studied, histologically, histochemically, ultramicroscopically, and electromyographically. In all three there is clinical evidence of skeletal muscle weakness, and in all three, pathologic changes were found in the muscle. These changes were different in each case and varied from mitochondrial myopathy to spinal atrophy to vacuolar myopathy. Other reported cases of cardiomyopathy demonstrating skeletal muscle pathology are discussed.

Treatment of Normal Skeletal Muscle with FK506 or Rapamycin Results in Halothane-induced Muscle Contracture

Background FKBP12 is a protein that is closely associated with the ryanodine receptor type 1 of skeletal muscle and modulates Ca2+ release by the channel. The immunosuppressants FK506 and rapamycin both bind to FKBP12 and in turn dissociate the protein from the ryanodine receptor. By treating healthy human skeletal muscle strips with FK506 or rapamycin and then subjectin the strips to the caffeine-halothane contracture test, this study determined that FK506 and rapamycin alter the sensitivity of the muscle strip to halothane, caffeine, or both. Methods Skeletal muscle strips from 10 healthy persons were incubated in Krebs medium equilibrated with a 95% oxygen and 5% carbon dioxide mixture, which contained either 12 [micro sign]M FK506 (n = 8) or 12 [micro sign]M rapamycin (n = 6), for 15 min at 37 [degree sign]C. The strips were subjected to the caffeine-halothane contracture test for malignant hyperthermia according to the European Malignant Hyperthermia Group protocol. Results Treatment of normal skeletal muscle strips with FK506 and rapamycin resulted in halothane-induced contractures of 0.44 +/- 0.16 g and 0.6 +/- 0.49 g, respectively, at 2% halothane. Conclusions The results obtained show that pre-exposure of healthy skeletal muscle strips to either FK506 or rapamycin is sufficient to give rise to halothane-induced contractures. This is most likely caused by destabilization of Ca2+ release by the ryanodine receptor as a result of the dissociation of FKBP12. This finding suggests that a mutation in FKBP12 or changes in its capacity of blind to the ryanodine receptor could alter the halothane sensitivity of the skeletal muscle ryanodine receptor and thereby predispose the person to malignant hyperthermia.

No abnormal low molecular weight proteins identified in human malignant hyperthermic muscle

There is no single, simple diagnostic test available to enable identification of malignant hyperthermia (MH) susceptible individuals. Recently, two novel low-molecular-weight proteins (15,000 daltons and 13,500 daltons) that were not present in normal muscle were identified in MH muscle and it was felt that this might eventually be of assistance in diagnosing MH. The authors of this report have been unable to verify these results. Polyacrylamide gel electrophoresis of the soluble proteins from muscle of four MH-susceptible and four normal individuals showed no differences in the electrophoretic fractionation patterns. Therefore, the authors conclude that the differences in protein composition previously reported in MH muscle are not characteristic of this syndrome.

Female carriers of Duchenne muscular dystrophy: a dilemma

In this paper female non‐identical twins of a known Duchenne carrier are presented; one has typical features and the anticipated progression of Duchenne dystrophy, the other appears to be normal. In addition, two female children with Duchenne‐like dystrophy are discussed. These cases show no evidence of translocation or mosaicism and offer an opportunity to reappraise the genetics of Duchenne dystrophy with specific regard to females. The subjects have been fully investigated, and in Case 3 the glycolytic enzymes and mitochondrial energy‐producing capacity were also studied.

Hereditary motor and sensory neuropathy type I, associated with aplasia cutis congenital possible X‐linked inheritance

Castle D, Isaacs H, Ramsay M, Bernstein R. Hereditary motor and sensory neuropathy type I, associated with aplasia cutis congenita: possible X‐linked inheritance. Clin Genet 1992:41: 108–110.

Kinase activity and protein phosphorylation in control and malignant hyperthermic skeletal muscle

1. Native 6% Laemmli gels were used to resolve 7 protein kinase activity bands in control and malignant hyperthermia (MH)-susceptible porcine and human skeletal muscle extracts. 2. MH-susceptible samples were consistently more active than the controls. 3. Following halothane treatment, a 43 kDa component displayed increased phosphorylation by a calcium-calmodulin dependent kinase in MH-susceptible vs control human samples. 4. Increased phosphorylation of additional endogenous protein components of molecular mass 116 and 60 kDa was observed.