Sphingomyelinase depresses force and calcium sensitivity of the contractile apparatus in mouse diaphragm muscle fibers

Leonardo F. Ferreira, Jennifer S. Moylan, Shawn Stasko, Jeffrey D. Smith, Kenneth S. Campbell, Michael B. Reid

Research output: Contribution to journalArticlepeer-review

25 Scopus citations

Abstract

Diseases that result in muscle weakness, e.g., heart failure, are characterized by elevated sphingomyelinase (SMase) activity. In intact muscle, SMase increases oxidants that contribute to diminished muscle force. However, the source of oxidants, specific processes of muscle contraction that are dysfunctional, and biochemical changes underlying the weakness elicited by SMase remain unknown. We tested three hypotheses: 1) SMase-induced depression of muscle force is mediated by mitochondrial reactive oxygen species (ROS), 2) SMase depresses force and calcium sensitivity of the contractile apparatus, and 3) SMase promotes oxidation and phosphorylation of myofibrillar proteins. Our experiments included intact muscle bundles, permeabilized single fibers, and isolated myofibrillar proteins. The mitochondrial-targeted antioxidant D-Arg-2′,6′-dimethyl-Tyr-Lys-Phe-NH 2, decreased cytosolic oxidants and protected intact muscle bundles from weakness stimulated by SMase. SMase depressed maximal calcium-activated force by 20% in permeabilized single fibers (in kN/m 2: control 117 ± 6; SMase 93 ± 8; P < 0.05). Calcium sensitivity of permeabilized single fibers decreased from 5.98 ± 0.03 (control) to 5.91 ± 0.02 (SMase; P < 0.05). Myofibrillar protein nitrotyrosines, carbonyls, and phosphorylation were unaltered by SMase. Our study shows that the fall in specific force of intact muscle elicited by SMase is mediated by mitochondrial ROS and can be attributed largely to dysfunction of the contractile apparatus.

Original languageEnglish
Pages (from-to)1538-1545
Number of pages8
JournalJournal of Applied Physiology
Volume112
Issue number9
DOIs
StatePublished - May 1 2012

Keywords

  • Mitochondria
  • Oxidative stress
  • Single fiber
  • Skeletal muscle
  • Sphingolipids

ASJC Scopus subject areas

  • General Medicine

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