Format

Send to

Choose Destination
J Cachexia Sarcopenia Muscle. 2019 Apr;10(2):411-428. doi: 10.1002/jcsm.12375. Epub 2019 Feb 1.

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

Author information

1
Aging and Metabolism Research Program, Oklahoma Medical Research Foundation, Oklahoma City, USA.
2
Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, USA.
3
Oklahoma Center for Neuroscience, University of Oklahoma Health Sciences Center, Oklahoma City, USA.
4
Department of Surgery, Section of Plastic Surgery, University of Michigan, Ann Arbor, USA.
5
Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, USA.
6
Reynolds Oklahoma Center on Aging, University of Oklahoma Health Sciences Center, Oklahoma City, USA.
7
Oklahoma City VA Medical Center, Oklahoma City, USA.

Abstract

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.

KEYWORDS:

Fibre branching; Hyperplasia; Mitochondria; MnSOD; Reactive oxygen species; Skeletal muscle

Supplemental Content

Full text links

Icon for Wiley Icon for PubMed Central
Loading ...
Support Center