Impaired organization and function of myofilaments in single muscle fibers from a mouse model of Pompe disease

Sengen Xu, Mikhail Galperin, Gary Melvin, Robert Horowits, Nina Raben, Paul Plotz, Leepo Yu

Research output: Contribution to journalArticle

Abstract

Pompe disease, a defi-ciency of lysosomal acid α-glucosidase, is a disorder of glycogen, metabolism that can affect infants, children, or adults. In all forms of the disease, there is progressive muscle pathology leading to premature death. The pathology is characterized by accumulation of glycogen in lysosomes, autophagic buildup, and muscle atrophy. The purpose of the present investigation was to determine if myofibrillar dysfunction in Pompe disease contributes to muscle weakness beyond that attributed to atrophy. The study was performed on isolated myofibers dissected from severely affected fast glycolytic muscle in the α-glucosidase knockout mouse model. Psoas muscle fibers were first permeabilized, so that the contractile proteins could be directly relaxed or activated by control of the composition of the bathing solution. When normalized by cross-sectional area, single fibers from, knockout mice produced 6.3 N/cm2 of maximum Ca2+-activated tension compared with 12.0 N/cm2 produced by wild-type fibers. The total protein concentration was slightly higher in the knockout mice, but concentrations of the contractile proteins myosin and actin remained unchanged. Structurally, X-ray diffraction showed that the actin and myosin filaments, normally arranged in hexagonal arrays, were disordered in the knockout muscle, and a lower fraction of myosin cross bridges was near the actin filaments in the relaxed muscle. The results are consistent with a disruption of actin and myosin interactions in the knockout muscles, demonstrating that impaired myofibrillar function contributes to weakness in the diseased muscle fibers.

Original languageEnglish (US)
Pages (from-to)1383-1388
Number of pages6
JournalJournal of Applied Physiology
Volume108
Issue number5
DOIs
StatePublished - May 2010
Externally publishedYes

Keywords

  • Actin-myosin interaction
  • Lysosomal glycogen storage disease

ASJC Scopus subject areas

  • Physiology
  • Physiology (medical)

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