Force generated by myosin cross-bridges is reduced in myofibrils exposed to ROS/RNS

Malin Persson1,2, Maarten M Steinz2, Håkan Westerblad2

  • 1Department of Kinesiology and Physical Education, McGill University, Montreal, Quebec, Canada.

Insights

Reactive oxygen and nitrogen species (ROS/RNS) impair skeletal muscle function by reducing myofibrillar force. This study shows peroxynitrite significantly decreases isometric force by altering cross-bridge dynamics.

Area of Science:

  • Muscle Physiology
  • Biochemistry
  • Oxidative Stress Research

Background:

  • Skeletal muscle weakness is linked to oxidative stress and modifications of contractile proteins.
  • Reactive oxygen/nitrogen species (ROS/RNS) are implicated in muscle dysfunction, but their acute effects on myosin-actin interactions are unclear.

Purpose of the Study:

  • To investigate the direct impact of peroxynitrite (ONOO-) on the contractile properties of isolated skeletal muscle myofibrils.
  • To elucidate the mechanisms by which ROS/RNS affect myofibrillar force production.

Main Methods:

  • Utilized atomic force microscopy to measure myofibril-induced displacements upon activation and relaxation.
  • Assessed the effects of ONOO- donors (SIN-1) and direct ONOO- application on myofibrillar force.
  • Analyzed changes in cross-bridge detachment rate (g_app) and force redevelopment rate (k_Tr).

Main Results:

  • Peroxynitrite treatment reduced isometric force by approximately 50%.
  • This force reduction was observed regardless of the cross-bridge condition (rigor or relaxing) during ONOO- exposure.
  • The decrease in force was attributed to an increased cross-bridge detachment rate, not a change in force redevelopment rate.

Conclusions:

  • ROS/RNS, specifically ONOO-, significantly impair skeletal muscle myofibrillar force production.
  • The findings highlight alterations in cross-bridge cycling kinetics as a key mechanism of ONOO--induced muscle weakness.
  • This research provides critical insights into the pathophysiology of conditions involving heightened oxidative stress.

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