Zidovudine [AZT] myotoxicity: quantitative separation of AZT effects on proliferation and differentiation of muscle cells in vitro. Lack of myotoxicity potentiation by retrovirus.

We compared quantitatively the myotoxicity of 3'-azido-2',3'-dideoxythymidine (AZT) against uninfected and ts1 retrovirus infected mouse skeletal muscle (ATCC CRL 1772) cells at different stages of maturation in vitro. The AZT half inhibitory concentration (IC50) for myoblast proliferation was determined for uninfected myoblasts and parallel cultures infected with ts1 virus. The AZT IC50 for muscle cell differentiation was determined in cultures where myoblasts were grown to confluence and then changed to the fusion medium to which AZT was added at increasing concentrations. Creatine kinase activity was used as a marker of muscle cell differentiation and was determined in homogenates after 7 days. Total cellular mitochondrial DNA was analyzed by Southern blotting. The estimated AZT IC50 for muscle cell proliferation (2-5 microM) was significantly less than the AZT IC50 for muscle cell differentiation (100 microM). Infection with ts1 retrovirus did not significantly shift the IC50 for either proliferation or differentiation of muscle cells. Toxic concentrations of AZT did not cause selective depletion of mitochondrial DNA. The myotoxic effects of AZT on myoblast proliferation and muscle cell differentiation in vitro were quantitatively different and were not changed by productive ts1 retrovirus infection of muscle cells. These results suggest that AZT may impair muscle fiber regeneration in the course of retrovirus associated myopathy. The mechanism of AZT myotoxicity was not explained by alterations in total mitochondrial DNA content.

Muscle pathology and clinical features of the sarcolemmopathies.

We report the clinical features and the muscle pathology in 2 patients with congenital muscular dystrophy (CMD) secondary to merosin deficiency and in 2 patients with sarcoglycan (adhalin) deficiency. Electron microscopic examination revealed sarcolemmal defects in non-necrotic muscle fibers in all cases. These pathological findings are indistinguishable from those of Duchenne/Becker muscular dystrophy. We suggest that the similarities in histological findings reflect a common pathogenetic mechanism, i.e., a structural weakening of the sarcolemma with an increased susceptibility to rupture under mechanical stress. We propose the term sarcolemmopathy as an all-encompassing rubric for these disorders.

CD8 and CD4 T cell-mediated polymyositis complicating the HTLV-1 associated myelopathy. Quantitative evaluation of corticosteroid treatment.

INTRODUCTION: Inflammatory myopathy is a treatable cause of worsening in the spectrum of neurological conditions that may develop during the course of HTLV-1 infection. MATERIAL AND METHODS: To investigate the cause of subacute worsening in the strength of a 46-y-old black male with HTLV-1 associated myelopathy we performed electrodiagnostic examination and a muscle biopsy which was studied with histochemistry, immunocytochemistry and electron microscopy. Serial measurements of isometric muscle strength were performed during the course of corticosteroid treatment. RESULTS: The muscle biopsy showed evidence of denervation atrophy and prominent inflammatory changes with autoaggressive features. Lymphocyte typing showed a predominance of CD8+ T cells. The patient had sustained, marked improvement in strength, especially of the upper extremities, with oral, high single-dose, alternate-day prednisone therapy. CONCLUSION: A muscle biopsy should be considered in all patients with HTLV-1 associated weakness, especially when electromyography indicates possible coexisting primary muscle involvement and/or serum creatine kinase levels are elevated. HTLV-1-associated polymyositis can be successfully treated with corticosteroids.

Congenital myopathy with ringlike distribution of myonuclei and mitochondria and accumulation of nemaline rods. A variant of centronuclear myopathy?

Histopathologic and ultrastructural findings in a muscle biopsy performed on an 11-year old boy with congenital hypotonia, weakness, respiratory insufficiency requiring chronic ventilatory support, and a probable X-linked inheritance are presented. The muscle biopsy disclosed a peculiar, ringlike arrangement of mitochondria and myonuclei in most muscle fibers. Accumulations of nemaline rods were present in approximately 10-15% of fibers. We believe that our patient represents a variant of myotubular/centronuclear myopathy. The histochemical findings suggest disturbance in developmental migration of nuclei and mitochondria probably due to impaired function of the cytoskeleton.

Probable herpesvirus infection in an eastern cottontail (Sylvilagus floridanus).

One wild eastern cottontail (Sylvilagus floridanus) from Milwaukee County, Wisconsin was necropsied. The lungs contained numerous multifocal, circumscribed, tan foci; the spleen was markedly enlarged and had a mottled reddish tan color; and the brain had a red to tan friable tract in the left hemisphere. Microscopically, the lung had a severe bronchiolitis and pneumonia. The bronchiolitis was characterized by epithelial cells containing eosinophilic intranuclear inclusion bodies. The encephalomalacia of the left cerebral cortex featured tissue disruption and astrocytes or neurons containing intranuclear inclusion bodies. Herpesvirus particles were found within the bronchiolar epithelial cells. Based on histopathological and ultrastructural findings, a herpesvirus seemed the most likely etiologic agent.