The sparing of extraocular muscle in dystrophinopathy is lost in mice lacking utrophin and dystrophin.

The extraocular muscles are one of few skeletal muscles that are structurally and functionally intact in Duchenne muscular dystrophy. Little is known about the mechanisms responsible for differential sparing or targeting of muscle groups in neuromuscular disease. One hypothesis is that constitutive or adaptive properties of the unique extraocular muscle phenotype may underlie their protection in dystrophinopathy. We assessed the status of extraocular muscles in the mdx mouse model of muscular dystrophy. Mice showed mild pathology in accessory extraocular muscles, but no signs of pathology were evident in the principal extraocular muscles at any age. By immunoblotting, the extraocular muscles of mdx mice exhibited increased levels of a dystrophin analog, dystrophin-related protein or utrophin. These data suggest, but do not provide mechanistic evidence, that utrophin mediates eye muscle protection. To examine a potential causal relationship, knockout mouse models were used to determine whether eye muscle sparing could be reversed. Mice lacking expression of utrophin alone, like the dystrophin-deficient mdx mouse, showed no pathological alterations in extraocular muscle. However, mice deficient in both utrophin and dystrophin exhibited severe changes in both the accessory and principal extraocular muscles, with the eye muscles affected more adversely than other skeletal muscles. Selected extraocular muscle fiber types still remained spared, suggesting the operation of an alternative mechanism for muscle sparing in these fiber types. We propose that an endogenous upregulation of utrophin is mechanistic in protecting extraocular muscle in dystrophinopathy. Moreover, data lend support to the hypothesis that interventions designed to increase utrophin levels may ameliorate the pathology in other skeletal muscles in Duchenne muscular dystrophy.

Oxidative stress as a potential pathogenic mechanism in an animal model of Duchenne muscular dystrophy.

Dystrophin-deficiency results in degeneration of most, but not all, skeletal muscles. The mechanisms responsible for degeneration of limb muscle and sparing of extraocular muscle are not known. To address the notion that muscle pathology may be free radical-mediated, we evaluated antioxidant enzyme activities and lipid peroxidation products (TBARS) content in mdx and control mice. TBARS content and the activities of total superoxide dismutase, selenium dependent glutathione peroxidase, glucose-6-phosphate dehydrogenase and catalase were consistently higher in both affected and spared muscles of mdx mice. These data suggest that oxidative stress may be constitutively present in mdx muscle, but may not be the principal pathogenic mechanism. To further test the hypothesis of oxidative stress involvement in dystrophinopathies, control strain and mdx mice were subjected to chronic hyperoxia. The pattern of antioxidant enzyme activities and TBARS content from hyperoxic control strain mice was similar to that of normoxic mdx mice, suggesting that a similar level of oxidative stress was induced. In conclusion, this study has provided indirect evidence for oxidative stress in dystrophin-deficient muscle.

Extraocular, limb and diaphragm muscle group-specific antioxidant enzyme activity patterns in control and mdx mice.

The mechanisms primarily responsible for the degenerative processes occurring in dystrophic skeletal muscle remain unresolved. The identification of the mechanisms that lead to the complete sparing of extraocular muscle in dystrophinopathies is of particular interest. A number of studies have provided evidence to suggest that the muscle pathology that characterizes muscular dystrophy may be, in part, free radical mediated. In the present study, we examined the antioxidant enzyme status of extraocular, diaphragm and gastrocnemius muscles in control strain and mdx mice. Our results revealed that in the control strain, both extraocular and diaphragm muscles had higher copper/zinc superoxide dismutase, manganese superoxide dismutase and selenium dependent glutathione peroxidase activities as compared to the gastrocnemius. Furthermore, the diaphragm had higher glutathione reductase activity as compared to the gastrocnemius. These findings indicate that the highly aerobic extraocular and diaphragm muscles have higher antioxidant enzyme capacity than the gastrocnemius, a muscle more dependent on anaerobic energy metabolism. Changes in the antioxidant enzyme status of the mdx mouse correlated, in part, with the degree of histopathological involvement of the three muscle groups assessed.

Extraocular muscles: basic and clinical aspects of structure and function.

Although extraocular muscle is perhaps the least understood component of the oculomotor system, these muscles represent the most common site of surgical intervention in the treatment of strabismus and other ocular motility disorders. This review synthesizes information derived from both basic and clinical studies in order to develop a better understanding of how these muscles may respond to surgical or pharmacological interventions and in disease states. In addition, a detailed knowledge of the structural and functional properties of extraocular muscle, that would allow some degree of prediction of the adaptive responses of these muscles, is vital as a basis to guide the development of new treatments for eye movement disorders.