Mitochondrial energy deficiency leads to hyperproliferation of skeletal muscle mitochondria and enhanced insulin sensitivity

Morrow, Ryan; Picard, Martin; Derbeneva, Olga; Leipzig, Jeremy; McManus, Meagan J.; Gouspillou, Gilles; Barbat‐Artigas, Sébastien; Santos, Carlos Pereira dos; Hepple, Russell T.; Murdock, Deborah G.; Wallace, Douglas C.

doi:10.1073/pnas.1700997114

Cited by 80 publications

(92 citation statements)

References 39 publications

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“…In line with the idea, our m Sod2 KO mice demonstrated mitochondrial proliferation (Figure A–C). An animal model leading to a significant mitochondrial dysfunction (ANT1KO) and compensatory proliferation exhibits redness of the muscle . Another animal model with PGC1‐α overexpression demonstrates increased pigment in skeletal muscle tissues .…”

Section: Resultsmentioning

confidence: 99%

“…An animal model leading to a significant mitochondrial dysfunction (ANT1KO) and compensatory proliferation exhibits redness of the muscle. 48 Another animal model with PGC1-α overexpression demonstrates increased pigment in skeletal muscle tissues. 49 Increase in muscle mass in gastrocnemius is not caused by a change in fibre size (i.e.…”

Section: Mitochondrial Oxidative Stress Increases Muscle Mass Via Hypmentioning

confidence: 99%

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

Ahn

Ranjit

Premkumar

et al. 2019

J cachexia sarcopenia muscle

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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 (m Sod2 KO) 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 m Sod2 KO 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 /cm 2 ), 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.

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Section: Resultsmentioning

confidence: 99%

Section: Mitochondrial Oxidative Stress Increases Muscle Mass Via Hypmentioning

confidence: 99%

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

Ahn

Ranjit

Premkumar

et al. 2019

J cachexia sarcopenia muscle

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“…Similar findings have been reported in other animal models where mitochondrial respiration is compromised and associated with reduced specific force capacity that is not a result of muscle atrophy (Gouspillou et al 2018). However, it should be noted that other models demonstrate muscle atrophy accompanied by reduced absolute force with reduced respiration kinetics, although a frequent key characteristic of these models is increased mortality (Diaz et al 2005;Morrow et al 2017). Mitochondrial respiratory dysfunction reported in Brca1KO smi mice was associated with increased Figure 7.…”

Section: Discussionmentioning

confidence: 95%

Induced in vivo knockdown of the Brca1 gene in skeletal muscle results in skeletal muscle weakness

Tarpey

Valencia

Jackson

et al. 2018

The Journal of Physiology

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Key points Breast cancer 1 early onset gene codes for the DNA repair enzyme, breast cancer type 1 susceptibility protein (BRCA1). The gene is prone to mutations that cause a loss of protein function. BRCA1/Brca1 has recently been found to regulate several cellular pathways beyond DNA repair and is expressed in skeletal muscle. Skeletal muscle specific knockout of Brca1 in mice caused a loss of muscle quality, identifiable by reductions in muscle force production and mitochondrial respiratory capacity. Loss of muscle quality was associated with a shift in muscle phenotype and an accumulation of mitochondrial DNA mutations. These results demonstrate that BRCA1 is necessary for skeletal muscle function and that increased mitochondrial DNA mutations may represent a potential underlying mechanism. Abstract Recent evidence suggests that the breast cancer 1 early onset gene (BRCA1) influences numerous peripheral tissues, including skeletal muscle. The present study aimed to determine whether induced‐loss of the breast cancer type 1 susceptibility protein (Brca1) alters skeletal muscle function. We induced genetic ablation of exon 11 in the Brca1 gene specifically in the skeletal muscle of adult mice to generate skeletal muscle‐specific Brca1 homozygote knockout (Brca1KOsmi) mice. Brca1KOsmi exhibited kyphosis and decreased maximal isometric force in limb muscles compared to age‐matched wild‐type mice. Brca1KOsmi skeletal muscle shifted toward an oxidative muscle fibre type and, in parallel, increased myofibre size and reduced capillary numbers. Unexpectedly, myofibre bundle mitochondrial respiration was reduced, whereas contraction‐induced lactate production was elevated in Brca1KOsmi muscle. Brca1KOsmi mice accumulated mitochondrial DNA mutations and exhibited an altered mitochondrial morphology characterized by distorted and enlarged mitochondria, and these were more susceptible to swelling. In summary, skeletal muscle‐specific loss of Brca1 leads to a myopathy and mitochondriopathy characterized by reductions in skeletal muscle quality and a consequent kyphosis. Given the substantial impact of BRCA1 mutations on cancer development risk in humans, a parallel loss of BRCA1 function in patient skeletal muscle cells would potentially result in implications for human health.

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“…; Morrow et al. ). Because until recently, T2DM was mainly prevalent in individuals over 50, most of the studies investigating the effects of HFD on mitochondrial function were performed in adult animals.…”

Section: Introductionmentioning

confidence: 98%

“…Among the underlying mechanisms, fat accumulation in muscle cells were shown to interfere with insulin signaling pathways, and therefore contribute to insulin resistance (Brons and Vaag 2009). Although controversies still remain, the accumulation of mitochondrial dysfunctions, including reactive oxygen species (ROS) over production, impaired energetics, and a reduced ability to oxidize fat, has been proposed to play a major role in this process (Anderson et al 2009;Morrow et al 2017). Because until recently, T2DM was mainly prevalent in individuals over 50, most of the studies investigating the effects of HFD on mitochondrial function were performed in adult animals.…”

Section: Introductionmentioning

confidence: 99%

The impact of a short-term high-fat diet on mitochondrial respiration, reactive oxygen species production, and dynamics in oxidative and glycolytic skeletal muscles of young rats

Leduc‐Gaudet

Reynaud²,

Chabot³

et al. 2018

Physiol Rep

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Multiple aspects of mitochondrial function and dynamics remain poorly studied in the skeletal muscle of pediatric models in response to a short-term high-fat diet (HFD). This study investigated the impact of a short-term HFD on mitochondrial function and dynamics in the oxidative soleus (SOL) and glycolytic extensor digitorum longus (EDL) muscles in young rats. Young male Wistar rats were submitted to either HFD or normal chow (NCD) diets for 14 days. Permeabilized myofibers from SOL and EDL were prepared to assess mitochondrial respiration and reactive oxygen species (ROS) production. The expression and content of protein involved in mitochondrial metabolism and dynamics (fusion/fission) were also quantified. While no effects of HFD was observed on mitochondrial respiration when classical complex I and II substrates were used, both SOL and EDL of rats submitted to a HFD displayed higher basal and ADP-stimulated respiration rates when Malate + Palmitoyl-L-carnitine were used as substrates. HFD did not alter ROS production and markers of mitochondrial content. The expression of CPT1b was significantly increased in SOL and EDL of HFD rats. Although the expression of UCP3 was increased in SOL and EDL muscles from HFD rats, mitochondrial coupling efficiency was not altered. In SOL of HFD rats, the transcript levels of Mfn2 and Fis1 were significantly upregulated. The expression and content of proteins regulating mitochondrial dynamics was not modulated by HFD in the EDL. Finally, DRP1 protein content was increased by over fourfold in the SOL of HFD rats. Taken altogether, our findings show that exposing young animals to short-term HFD results in an increased capacity of skeletal muscle mitochondria to oxidize fatty acids, without altering ROS production, coupling efficiency, and mitochondrial content. Our results also highlight that the impact of HFD on mitochondrial dynamics appears to be muscle specific.

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Mitochondrial energy deficiency leads to hyperproliferation of skeletal muscle mitochondria and enhanced insulin sensitivity

Cited by 80 publications

References 39 publications

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

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

Induced in vivo knockdown of the Brca1 gene in skeletal muscle results in skeletal muscle weakness

The impact of a short-term high-fat diet on mitochondrial respiration, reactive oxygen species production, and dynamics in oxidative and glycolytic skeletal muscles of young rats

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