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We evaluated the effect of adjunctive clenbuterol treatment on cation\u2010independent mannose\u20106\u2010phosphate receptor (CI\u2010MPR)\u2010mediated uptake and intracellular trafficking of GAA during muscle\u2010specific GAA expression with an adeno\u2010associated virus (AAV) vector in GAA\u2010knockout (KO) mice. Clenbuterol, which increases expression of CI\u2010MPR in muscle, was administered with the AAV vector. This combination therapy increased latency during rotarod and wirehang testing at 12 wk, in comparison with vector alone. The mean urinary glucose tetrasaccharide (Glc4), a urinary biomarker, was lower in GAA\u2010KO mice following combination therapy, compared with vector alone. Similarly, glycogen content was lower in cardiac and skeletal muscle following 12 wk of combination therapy in heart, quadriceps, diaphragm, and soleus, compared with vector alone. These data suggested that clenbuterol treatment enhanced trafficking of GAA to lysosomes, given that GAA was expressed within myofibers. The integral role of CI\u2010MPR was demonstrated by the lack of effectiveness from clenbuterol in GAA\u2010KO mice that lacked CI\u2010MPR in muscle, where it failed to reverse the high glycogen content of the heart and diaphragm or impaired wirehang performance. However, the glycogen content of skeletal muscle was reduced by the addition of clenbuterol in the absence of CI\u2010MPR, as was lysosomal vacuolation, which correlated with increased AKT signaling. In summary, \u03b2\n                    <jats:sub>2<\/jats:sub>\n                    \u2010agonist treatment enhanced CI\u2010MPR\u2010mediated uptake and trafficking of GAA in mice with Pompe disease, and a similarly enhanced benefit might be expected in other lysosomal storage disorders.\u2014Farah, B. L., Madden, L., Li, S., Nance, S., Bird, A., Bursac, N., Yen, P. M., Young, S. P., Koeberl, D. D. Adjunctive \u03b22\u2010agonist treatment reduces glycogen independently of receptor\u2010mediated acid \u03b1\u2010glucosidase uptake in the limb muscles of mice with Pompe disease.\n                    <jats:italic>FASEB J<\/jats:italic>\n                    . 28, 2272\u20132280 (2014).\n                    <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"http:\/\/www.fasebj.org\">www.fasebj.org<\/jats:ext-link>\n                  <\/jats:p>","DOI":"10.1096\/fj.13-244202","type":"journal-article","created":{"date-parts":[[2014,1,21]],"date-time":"2014-01-21T23:04:58Z","timestamp":1390345498000},"page":"2272-2280","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Adjunctive \u03b2\n                    <sub>2<\/sub>\n                    \u2010agonist treatment reduces glycogen independently of receptor\u2010mediated acid \u03b1\u2010glucosidase uptake in the limb muscles of mice with Pompe disease"],"prefix":"10.1096","volume":"28","author":[{"given":"Benjamin L.","family":"Farah","sequence":"first","affiliation":[{"name":"Cardiovascular and Metabolic Disease Program Duke\u2013National University of Singapore Graduate Medical School Singapore Singapore"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lauran","family":"Madden","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering Duke University Medical Center Durham North Carolina USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Songtao","family":"Li","sequence":"additional","affiliation":[{"name":"Division of Medical Genetics Department of Pediatrics Duke University Medical Center Durham North Carolina USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sierra","family":"Nance","sequence":"additional","affiliation":[{"name":"Division of Medical Genetics Department of Pediatrics Duke University Medical Center Durham North Carolina USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andrew","family":"Bird","sequence":"additional","affiliation":[{"name":"Division of Medical Genetics Department of Pediatrics Duke University Medical Center Durham North Carolina USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nenad","family":"Bursac","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering Duke University Medical Center Durham North Carolina USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Paul M.","family":"Yen","sequence":"additional","affiliation":[{"name":"Cardiovascular and Metabolic Disease Program Duke\u2013National University of Singapore Graduate Medical School Singapore Singapore"},{"name":"Sarah W. 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