Aerobic training as an adjunctive therapy to enzyme replacement in Pompe disease

Nilsson, Mats I.; Samjoo, Imtiaz A.; Hettinga, Bart P.; Koeberl, Dwight D.; Zhang, Haoyue; Hawke, Thomas J.; Nissar, Aliyah A.; Ali, Tahir Osman; Brandt, Linda; Ansari, M.U.; Hazari, Hassan; Patel, Neha; Amon, Jaihoon; Tarnopolsky, Mark A.

doi:10.1016/j.ymgme.2012.09.010

Cited by 31 publications

(17 citation statements)

References 59 publications

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“…In addition, the reduction in ventricular hypertrophy might not be related to glycogen clearance, because glycogen content in the heart was similar between propranolol-treated mice and those treated with ERT alone or clenbuterol and ERT (Figure 3B). Intriguingly, a beneficial effect of exercise independent of glycogen clearance was reported during ERT in GAA-KO mice 29 . Therefore, we consider glycogen accumulation to be an index of severity of Pompe disease, but accumulated glycogen itself might not be the cause for muscle involvement including cardiac hypertrophy and atrophy of skeletal muscle.…”

Section: Discussionmentioning

confidence: 99%

A beta-blocker, propranolol, decreases the efficacy from enzyme replacement therapy in Pompe disease

Han

Pope

et al. 2016

Molecular Genetics and Metabolism

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Enzyme replacement therapy (ERT) with recombinant human acid α-glucosidase (rhGAA) fails to completely reverse muscle weakness in Pompe disease. β2-agonists enhanced ERT by increasing receptor-mediated uptake of rhGAA in skeletal muscles. Purpose To test the hypothesis that a β-blocker might reduce the efficacy of ERT, because the action of β-blockers opposes those of β2-agonists. Methods Mice with Pompe disease were treated with propranolol (a β-blocker) or clenbuterol in combination with ERT, or with ERT alone. Results Propranolol-treated mice had decreased weight gain (p<0.01), in comparison with clenbuterol-treated mice. Left ventricular mass was decreased (and comparable to wild-type) in ERT only and clenbuterol-treated groups of mice, and unchanged in propranolol-treated mice. GAA activity increased following either clenbuterol or propranolol in skeletal muscles. However, muscle glycogen was reduced only in clenbuterol-treated mice, not in propranolol-treated mice. Cell-based experiments confirmed that propranolol reduces uptake of rhGAA into Pompe fibroblasts and also demonstrated that the drug induces intracellular accumulation of glycoproteins at higher doses. Conclusion Propranolol, a commonly prescribed β-blocker, increased left ventricular mass and decreased glycogen clearance in skeletal muscle following ERT. β-blockers might therefore decrease the efficacy from ERT in patients with Pompe disease.

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Section: Discussionmentioning

confidence: 99%

A beta-blocker, propranolol, decreases the efficacy from enzyme replacement therapy in Pompe disease

Han

Pope

et al. 2016

Molecular Genetics and Metabolism

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“…Differences between T2 and T3 were used to assess the effectiveness of the exercise during the infusion. enzyme together with exercise, there was no increase of the concentration of the recombinant enzyme in the muscles of experimental animals [8]. These data taken together suggest that the blood flow towards the skeletal muscles may not be the limiting factor for the effective delivery/action of the recombinant enzyme to the skeletal muscles and the enhancement of their functional capacity.…”

Section: Discussionmentioning

confidence: 76%

“…It has been postulated that this restrained effect of ERT might be linked to a limited blood flow to the resting skeletal muscles during infusion [8]. Exercise training induces rapid and significant increase in blood flow to the exercising skeletal muscles which continue for several minutes after the end of the training session [9].…”

Section: Introductionmentioning

confidence: 99%

Effects of exercise training during infusion on late-onset Pompe disease patients receiving enzyme replacement therapy

Terzis

Krase

Papadimas

et al. 2012

Molecular Genetics and Metabolism

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“…Cytochrome c oxidase (COX; EC 1.9.3.1), complex I+III, and citrate synthase (CS; EC 2.3.3.1) activities were measured in quadriceps homogenates as previously described by our group [28], [29], [30]. All samples were analyzed in duplicate on a Cary 300 Bio UV–visible spectrophotometer (Varion, Inc., Palo Alto, CA) and the intra-assay coefficient of variation for all samples was less than 5%.…”

Section: Methodsmentioning

confidence: 99%

Redox State and Mitochondrial Respiratory Chain Function in Skeletal Muscle of LGMD2A Patients

et al. 2014

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BackgroundCalpain-3 deficiency causes oxidative and nitrosative stress-induced damage in skeletal muscle of LGMD2A patients, but mitochondrial respiratory chain function and anti-oxidant levels have not been systematically assessed in this clinical population previously.MethodsWe identified 14 patients with phenotypes consistent with LGMD2A and performed CAPN3 gene sequencing, CAPN3 expression/autolysis measurements, and in silico predictions of pathogenicity. Oxidative damage, anti-oxidant capacity, and mitochondrial enzyme activities were determined in a subset of muscle biopsies.ResultsTwenty-one disease-causing variants were detected along the entire CAPN3 gene, five of which were novel (c.338 T>C, c.500 T>C, c.1525-1 G>T, c.2115+4 T>G, c.2366 T>A). Protein- and mRNA-based tests confirmed in silico predictions and the clinical diagnosis in 75% of patients. Reductions in antioxidant defense mechanisms (SOD-1 and NRF-2, but not SOD-2), coupled with increased lipid peroxidation and protein ubiquitination, were observed in calpain-3 deficient muscle, indicating a redox imbalance primarily affecting non-mitochondrial compartments. Although ATP synthase levels were significantly lower in LGMD2A patients, citrate synthase, cytochrome c oxidase, and complex I+III activities were not different from controls.ConclusionsDespite significant oxidative damage and redox imbalance in cytosolic/myofibrillar compartments, mitochondrial respiratory chain function is largely maintained in skeletal muscle of LGMD2A patients.

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Aerobic training as an adjunctive therapy to enzyme replacement in Pompe disease

Cited by 31 publications

References 59 publications

A beta-blocker, propranolol, decreases the efficacy from enzyme replacement therapy in Pompe disease

A beta-blocker, propranolol, decreases the efficacy from enzyme replacement therapy in Pompe disease

Effects of exercise training during infusion on late-onset Pompe disease patients receiving enzyme replacement therapy

Redox State and Mitochondrial Respiratory Chain Function in Skeletal Muscle of LGMD2A Patients

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