Mitochondrial oxidative stress impairs contractile function but paradoxically increases muscle mass via fibre branching

• Published in: Journal of cachexia, sarcopenia and muscle Vol. 10; no. 2; pp. 411 - 428
• Main Authors: Ahn, Bumsoo, Ranjit, Rojina, Premkumar, Pavithra, Pharaoh, Gavin, Piekarz, Katarzyna M., Matsuzaki, Satoshi, Claflin, Dennis R., Riddle, Kaitlyn, Judge, Jennifer, Bhaskaran, Shylesh, Satara Natarajan, Kavithalakshmi, Barboza, Erika, Wronowski, Benjamin, Kinter, Michael, Humphries, Kenneth M., Griffin, Timothy M., Freeman, Willard M., Richardson, Arlan, Brooks, Susan V., Van Remmen, Holly
• Format: Journal Article
• Language: English
• Published: Germany John Wiley & Sons, Inc 01.04.2019; John Wiley and Sons Inc; Wiley
• Subjects: Adenosine triphosphate; Atrophy; Endoplasmic reticulum; Fibre branching; Hydrogen peroxide; Hyperplasia; Methods; Mitochondria; MnSOD; Musculoskeletal system; Original; Oxidative stress; Proteins; Reactive oxygen species; Sarcopenia; Skeletal muscle; Oklahoma; Mitochondria; Reactive oxygen species; Fibre branching; Hyperplasia; Skeletal muscle; MnSOD
• ISSN: 2190-5991; 2190-6009
• DOI: 10.1002/jcsm.12375

Background Excess reactive oxygen species (ROS) and muscle weakness occur in parallel in multiple pathological conditions. However, the causative role of skeletal muscle mitochondrial ROS (mtROS) on neuromuscular junction (NMJ) morphology and function and muscle weakness has not been directly investigated. Methods We generated mice lacking skeletal muscle‐specific manganese‐superoxide dismutase (mSod2KO) to increase mtROS using a cre‐Lox approach driven by human skeletal actin. We determined primary functional parameters of skeletal muscle mitochondrial function (respiration, ROS, and calcium retention capacity) using permeabilized muscle fibres and isolated muscle mitochondria. We assessed contractile properties of isolated skeletal muscle using in situ and in vitro preparations and whole lumbrical muscles to elucidate the mechanisms of contractile dysfunction. Results The mSod2KO mice, contrary to our prediction, exhibit a 10–15% increase in muscle mass associated with an ~50% increase in central nuclei and ~35% increase in branched fibres (P < 0.05). Despite the increase in muscle mass of gastrocnemius and quadriceps, in situ sciatic nerve‐stimulated isometric maximum‐specific force (N/cm2), force per cross‐sectional area, is impaired by ~60% and associated with increased NMJ fragmentation and size by ~40% (P < 0.05). Intrinsic alterations of components of the contractile machinery show elevated markers of oxidative stress, for example, lipid peroxidation is increased by ~100%, oxidized glutathione is elevated by ~50%, and oxidative modifications of myofibrillar proteins are increased by ~30% (P < 0.05). We also find an approximate 20% decrease in the intracellular calcium transient that is associated with specific force deficit. Excess superoxide generation from the mitochondrial complexes causes a deficiency of succinate dehydrogenase and reduced complex‐II‐mediated respiration and adenosine triphosphate generation rates leading to severe exercise intolerance (~10 min vs. ~2 h in wild type, P < 0.05). Conclusions Increased skeletal muscle mtROS is sufficient to elicit NMJ disruption and contractile abnormalities, but not muscle atrophy, suggesting new roles for mitochondrial oxidative stress in maintenance of muscle mass through increased fibre branching.