title: Mechanism of neuromuscular dysfunction in Krabbe disease.
abstract: The atrophy of skeletal muscles in patients with Krabbe disease is a major debilitating manifestation that worsens their quality of life and limits the clinical efficacy of current therapies. The pathogenic mechanism triggering muscle wasting is unknown. This study examined structural, functional, and metabolic changes conducive to muscle degeneration in Krabbe disease using the murine (twitcher mouse) and canine [globoid cell leukodystrophy (GLD) dog] models. Muscle degeneration, denervation, neuromuscular [neuromuscular junction (NMJ)] abnormalities, and axonal death were investigated using the reporter transgenic twitcher-Thy1.1-yellow fluorescent protein mouse. We found that mutant muscles had significant numbers of smaller-sized muscle fibers, without signs of regeneration. Muscle growth was slow and weak in twitcher mice, with decreased maximum force. The NMJ had significant levels of activated caspase-3 but limited denervation. Mutant NMJ showed reduced surface areas and lower volumes of presynaptic terminals, with depressed nerve control, increased miniature endplate potential (MEPP) amplitude, decreased MEPP frequency, and increased rise and decay rate constants. Twitcher and GLD dog muscles had significant capacity to store psychosine, the neurotoxin that accumulates in Krabbe disease. Mechanistically, muscle defects involved the inactivation of the Akt pathway and activation of the proteasome pathway. Our work indicates that muscular dysfunction in Krabbe disease is compounded by a pathogenic mechanism involving at least the failure of NMJ function, activation of proteosome degradation, and a reduction of the Akt pathway. Akt, which is key for muscle function, may constitute a novel target to complement in therapies for Krabbe disease.
authors: Departments of Anatomy and Cell Biology.
authors: Ludovico
authors: L
authors: Cantuti-Castelvetri
authors: Departments of Anatomy and Cell Biology.
authors: Erick
authors: E
authors: Maravilla
authors: Departments of Anatomy and Cell Biology, Medical Scientist Training Program, University of Illinois at Chicago, Chicago, Illinois 60612, and.
authors: Michael
authors: M
authors: Marshall
authors: Physiology and Biophysics, and Medical Scientist Training Program, University of Illinois at Chicago, Chicago, Illinois 60612, and.
authors: Tammy
authors: T
authors: Tamayo
authors: Departments of Anatomy and Cell Biology.
authors: Ludovic
authors: http://orcid.org/0000-0001-6270-7739
authors: L
authors: D'auria
authors: Physiology and Biophysics, and.
authors: John
authors: J
authors: Monge
authors: Physiology and Biophysics, and.
authors: James
authors: J
authors: Jeffries
authors: Departments of Anatomy and Cell Biology.
authors: Tuba
authors: T
authors: Sural-Fehr
authors: Departments of Anatomy and Cell Biology.
authors: Aurora
authors: A
authors: Lopez-Rosas
authors: Medicinal Chemistry and Pharmacognosy and Medical Scientist Training Program, University of Illinois at Chicago, Chicago, Illinois 60612, and.
authors: Guannan
authors: G
authors: Li
authors: Physiology and Biophysics, and.
authors: Kelly
authors: http://orcid.org/0000-0001-8654-2588
authors: K
authors: Garcia
authors: Medicinal Chemistry and Pharmacognosy and Medical Scientist Training Program, University of Illinois at Chicago, Chicago, Illinois 60612, and.
authors: Richard
authors: R
authors: van Breemen
authors: School of Veterinary Medicine, University of Pennsylvania, Philadelphia 19104.
authors: Charles
authors: C
authors: Vite
authors: Physiology and Biophysics, and.
authors: Jesus
authors: J
authors: Garcia
authors: Departments of Anatomy and Cell Biology, ebongarz@uic.edu.
authors: Ernesto R
authors: ER
authors: Bongarzone
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001369:Axons / Q000378:metabolism / Q000473:pathology; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004285:Dogs; D005698:Galactosylceramidase / Q000235:genetics; D005786:Gene Expression Regulation / Q000235:genetics; D007965:Leukodystrophy, Globoid Cell / Q000150:complications* / Q000235:genetics / Q000473:pathology*; D008164:Luminescent Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D032342:Muscle Cells / Q000187:drug effects / Q000378:metabolism; D009119:Muscle Contraction / Q000235:genetics; D018482:Muscle, Skeletal / Q000254:growth & development; D009468:Neuromuscular Diseases / Q000209:etiology* / Q000378:metabolism* / Q000473:pathology; D011609:Psychosine / Q000378:metabolism; D011978:Receptors, Nicotinic / Q000235:genetics / Q000378:metabolism; D055366:Synaptic Potentials / Q000187:drug effects / Q000235:genetics
chemical_list: D001426:Bacterial Proteins; D008164:Luminescent Proteins; D011978:Receptors, Nicotinic; C559497:acetylcholine receptor gamma, mouse; C054562:yellow fluorescent protein, Bacteria; D011609:Psychosine; D005698:Galactosylceramidase
keywords: Akt; Krabbe disease; neuromuscular junction; neuropathy; proteosome; psychosine
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