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McArdle disease is caused by a deficiency of myophosphorylase and currently a satisfactory treatment is not available. The injection of notexin into, or the layering of notexin onto, the muscles of affected sheep resulted in necrosis followed by regeneration of muscle fibres with the expression of both non-muscle isoforms of phosphorylase within the fibres and a reduction of the amount of glycogen in the muscle with an increase in the strength of contraction and a decrease in fatiguability in the muscle fibres. The sustained re-expression of both the brain and liver isoforms of phosphorylase within the muscle fibres provides further emphasis that strategies to enhance the re-expression of these isoforms should be investigated as a possible treatment for McArdle disease., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Background: Ethanol neurobehavioural teratogenicity is a leading cause of developmental mental deficiency, in which the hippocampus is a target site of injury. The multi-faceted mechanism of ethanol teratogenicity is not completely understood. This study tested the hypothesis that chronic ethanol exposure (CEE), via chronic maternal ethanol administration, increases cytochrome P450 2E1 (CYP2E1) expression and alters hypothalamic-pituitary-adrenal (HPA) axis activity in the maternal-fetal unit during the third-trimester-equivalent of gestation., Methods: Pregnant Dunkin-Hartley-strain guinea pigs received daily oral administration of ethanol (4 g ethanol/kg maternal body weight) or isocaloric-sucrose/pair-feeding (control) throughout gestation (term, about gestational day (GD) 68). On GD 45, 55 and 65, pregnant animals were euthanized 2h after the last daily dose. Maternal and fetal body weights and fetal hippocampal brain weight were determined. Maternal and fetal samples were collected for the determination of liver CYP2E1 enzymatic activity and plasma free cortisol and ACTH concentrations., Results: CEE, with maternal blood ethanol concentration of 108-124 mg/dl at 2h after the last dose, decreased fetal hippocampal weight only at GD 65 and had no effect on fetal body weight compared with control. CYP2E1 activity increased with gestational age in the fetal liver microsomal and mitochondrial fractions. CEE increased CYP2E1 activity in the microsomal and mitochondrial fractions of maternal liver at the three gestational ages and in both hepatic subcellular fractions of the GD 65 fetus compared with control. There was a gestational-age-dependent increase in maternal and fetal plasma free cortisol concentrations, but no effect of CEE compared with control. Maternal and fetal plasma ACTH concentrations were unaffected by CEE compared with control, and were virtually unchanged during the third-trimester-equivalent that was studied., Conclusion: These data demonstrate that, in the pregnant guinea pig, this CEE regimen increases liver CYP2E1 activity, without affecting HPA axis function, in the maternal-fetal unit during near-term gestation. The CEE-induced increase in liver CYP2E1 activity and potential oxidative stress in the maternal-fetal unit may play a role in the pathogenesis of ethanol teratogenicity., (Copyright (c) 2009 Elsevier Inc. All rights reserved.)

As with many skeletal muscle diseases, the extraocular muscles (EOMs) are spared in skeletal muscle alpha-actin diseases, with no ophthalmoplegia even in severely affected patients. We hypothesised that the extraocular muscles sparing in these patients was due to significant expression of cardiac alpha-actin, the alpha-actin isoform expressed in heart and foetal skeletal muscle. We have shown by immunochemistry, Western blotting and a novel MRM-mass spectrometry technique, comparable levels of cardiac alpha-actin in the extraocular muscles of human, pig and sheep to those in the heart. The sparing of extraocular muscles in skeletal muscle alpha-actin disease is thus probably due to greater levels of cardiac alpha-actin, than the negligible amounts in skeletal muscles, diluting out the effects of the mutant skeletal muscle alpha-actin.

At present there is no satisfactory treatment for McArdle's disease, deficiency of myophosphorylase. Injection of modified adenovirus 5 (AdV5) and adeno-associated virus 2 (AAV2) vectors containing myophosphorylase expression cassettes, into semitendinosus muscle of sheep with McArdle's disease, produced expression of functional myophosphorylase and some re-expression of the non-muscle glycogen phosphorylase isoforms (both liver and brain) in regenerating fibres. Expression of both non-muscle isoforms was also seen after control injections of AdV5LacZ vectors. There was up to an order of magnitude greater expression of phosphorylase after myophosphorylase vector injection than after LacZ controls (62% of sections with over 1000 positive muscle fibres, versus 7%). The results presented here suggest that the use of viral vector-mediated phosphorylase gene transfer may be applicable to the treatment of McArdle's disease and that sustained re-expression of the brain and liver isoforms should also be investigated as a possible treatment.