Functional deficits in nNOSμ-deficient skeletal muscle: Myopathy in nNOS knockout mice

Justin M. Percival, Kendra N.E. Anderson, Paul Gregorevic, Jeffrey S. Chamberlain, Stanley C. Froehner

Research output: Contribution to journalArticle

68 Scopus citations

Abstract

Skeletal muscle nNOSμ (neuronal nitric oxide synthase mu) localizes to the sarcolemma through interaction with the dystrophin-associated glycoprotein (DAG) complex, where it synthesizes nitric oxide (NO). Disruption of the DAG complex occurs in dystrophinopathies and sarcoglycanopathies, two genetically distinct classes of muscular dystrophy characterized by progressive loss of muscle mass, muscle weakness and increased fatigability. DAG complex instability leads to mislocalization and downregulation of nNOSμ; but this is thought to play a minor role in disease pathogenesis. This view persists without knowledge of the role of nNOS in skeletal muscle contractile function in vivo and has influenced gene therapy approaches to dystrophinopathy, the majority of which do not restore sarcolemmal nNOSμ. We address this knowledge gap by evaluating skeletal muscle function in nNOS knockout (KN1) mice using an in situ approach, in which the muscle is maintained in its normal physiological environment. nNOS-deficiency caused reductions in skeletal muscle bulk and maximum tetanic force production in male mice only. Furthermore, nNOS-deficient muscles from both male and female mice exhibited increased susceptibility to contraction-induced fatigue. These data suggest that aberrant nNOSμ signaling can negatively impact three important clinical features of dystrophinopathies and sarcoglycanopathies: maintenance of muscle bulk, force generation and fatigability. Our study suggests that restoration of sarcolemmal nNOSμ expression in dystrophic muscles may be more important than previously appreciated and that it should be a feature of any fully effective gene therapy-based intervention.

Original languageEnglish (US)
Article numbere3387
JournalPloS one
Volume3
Issue number10
DOIs
StatePublished - Oct 13 2008

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

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    Percival, J. M., Anderson, K. N. E., Gregorevic, P., Chamberlain, J. S., & Froehner, S. C. (2008). Functional deficits in nNOSμ-deficient skeletal muscle: Myopathy in nNOS knockout mice. PloS one, 3(10), [e3387]. https://doi.org/10.1371/journal.pone.0003387