Dataset Information

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

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.

SUBMITTER: Ahn B

PROVIDER: S-EPMC6463475 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

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

Ahn Bumsoo B Ranjit Rojina R Premkumar Pavithra P Pharaoh Gavin G Piekarz Katarzyna M KM Matsuzaki Satoshi S Claflin Dennis R DR Riddle Kaitlyn K Judge Jennifer J Bhaskaran Shylesh S Satara Natarajan Kavithalakshmi K Barboza Erika E Wronowski Benjamin B Kinter Michael M Humphries Kenneth M KM Griffin Timothy M TM Freeman Willard M WM Richardson Arlan A Brooks Susan V SV Van Remmen Holly H

Journal of cachexia, sarcopenia and muscle 20190201 2

<h4>Background</h4>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.<h4>Methods</h4>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 ...[more]

PMID: 30706998

Similar Datasets

Project description:In the present study, we investigated the influence of diquat-induced oxidative stress on intestinal barrier, mitochondrial function, and the level of mitophagy in piglets. Twelve male Duroc × Landrace × Yorkshire 35-d-old pigs (weaned at 21 d of age), with an average body of 9.6 kg, were allotted to two treatments of six piglets each including the challenged group and the control group. The challenged pigs were injected with 100 mg/kg bodyweight diquat and control pigs injected with 0.9% (w/v) NaCl solution. The results showed that diquat injection decreased ADFI and ADG. Diquat decreased (P < 0.05) the activities of superoxide dismutase and glutathione peroxidase and increased (P < 0.05) the malondialdehyde concentrations. The lower (P < 0.05) transepithelial electrical resistance and higher (P < 0.05) paracellular permeability of fluorescein isothiocyanatedextran 4 kDa were found in diquat challenged piglets. Meanwhile, diquat decreased (P < 0.05) the protein abundance of claudin-1, occluding, and zonula occludens-1 in jejunum compared with the control group. Diquat-induced mitochondrial dysfunction, as demonstrated by increased (P < 0.05) reactive oxygen species production and decreased (P < 0.05) membrane potential of intestinal mitochondria. Diquat-injected pigs revealed a decrease (P < 0.05) of mRNA abundance of genes related to mitochondrial biogenesis and functions, PPARg coactivator-1α, mammalian-silencing information regulator-1, nuclear respiratory factor-1, mt transcription factor A, mt single-strand DNA-binding protein, mt polymerase r, glucokinase, citrate synthase, ATP synthase, and cytochrome coxidase subunit I and V in the jejunum. Diquat induced an increase (P < 0.05) in expression of mitophagy-related proteins, phosphatase and tensin homologue deleted on chromosome 10-induced putative kinase, and Parkin in the intestinal mitochondria, as well as an enhancement of the ratio of light chain 3-II (LC3-II) to LC3-I content in the jejunal mucosa. These results suggest that oxidative stress disrupted the intestinal barrier, caused mitochondrial dysfunction, and triggered mitophagy.

Project description:Key pointsHeart failure is characterised by limb and respiratory muscle impairments that limit functional capacity and quality of life. However, compared with heart failure with reduced ejection fraction (HFrEF), skeletal muscle alterations induced by heart failure with preserved ejection fraction (HFpEF) remain poorly explored. Here we report that obese-HFpEF induces multiple skeletal muscle alterations in the rat hindlimb, including impaired muscle mechanics related to shortening velocity, fibre atrophy, capillary loss, and an impaired blood flow response to contractions that implies a perfusive oxygen delivery limitation. We also demonstrate that obese-HFpEF is characterised by diaphragmatic alterations similar to those caused by denervation - atrophy in Type IIb/IIx (fast/glycolytic) fibres and hypertrophy in Type I (slow/oxidative) fibres. These findings extend current knowledge in HFpEF skeletal muscle physiology, potentially underlying exercise intolerance, which may facilitate future therapeutic approaches.AbstractPeripheral skeletal muscle and vascular alterations induced by heart failure with preserved ejection fraction (HFpEF) remain poorly identified, with limited therapeutic targets. This study used a cardiometabolic obese-HFpEF rat model to comprehensively phenotype skeletal muscle mechanics, blood flow, microvasculature and fibre atrophy. Lean (n = 8) and obese-HFpEF (n = 8) ZSF1 rats were compared. Skeletal muscles (soleus and diaphragm) were assessed for in vitro contractility (isometric and isotonic properties) alongside indices of fibre-type cross-sectional area, myosin isoform, and capillarity, and estimated muscle PO2 . In situ extensor digitorum longus (EDL) contractility and femoral blood flow were assessed. HFpEF soleus demonstrated lower absolute maximal force by 22%, fibre atrophy by 24%, a fibre-type shift from I to IIa, and a 17% lower capillary-to-fibre ratio despite increased capillary density (all P < 0.05) with preserved muscle PO2 (P = 0.115) and isometric specific force (P > 0.05). Soleus isotonic properties (shortening velocity and power) were impaired by up to 17 and 22%, respectively (P < 0.05), while the magnitude of the exercise hyperaemia was attenuated by 73% (P = 0.012) in line with higher muscle fatigue by 26% (P = 0.079). Diaphragm alterations (P < 0.05) included Type IIx fibre atrophy despite Type I/IIa fibre hypertrophy, with increased indices of capillarity alongside preserved contractile properties during isometric, isotonic, and cyclical contractions. In conclusion, obese-HFpEF rats demonstrated blunted skeletal muscle blood flow during contractions in parallel to microvascular structural remodelling, fibre atrophy, and isotonic contractile dysfunction in the locomotor muscles. In contrast, diaphragm phenotype remained well preserved. This study identifies numerous muscle-specific impairments that could exacerbate exercise intolerance in obese-HFpEF.

Dataset Information

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

Background

Methods

Results

Conclusions

Publications

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets