bims-misrem 2020-09-13 papers

bims-misrem

Biomed News

on Mitochondria and sarcoplasmic reticulum in muscle mass

Issue of 2020–09–13
twelve papers selected by
Rafael Antonio Casuso Pérez, University of Granada

Changes in Muscle Mass and Composition by Exercise and Hypoxia as Assessed by DEXA in Mice.
High-dose leucine supplementation does not prevent muscle atrophy or strength loss over 7 days of immobilization in healthy young males.
Atf-6 Regulates Lifespan through ER-Mitochondrial Calcium Homeostasis.
The eIF2α kinase HRI in innate immunity, proteostasis and mitochondrial stress.
Mitochondrial Contact Sites in Inflammation-Induced Cardiovascular Disease.
Mitochondrial-derived peptides in aging and age-related diseases.
SLC25A51 is a mammalian mitochondrial NAD+ transporter.
Differential effects of pre-exercise on cancer cachexia-induced muscle atrophy in fast- and slow-twitch muscles.
Redox modification of ryanodine receptor contributes to impaired Ca2+ homeostasis and exacerbates muscle atrophy under high altitude.
The phenotype associated with variants in TANGO2 may be explained by a dual role of the protein in ER-to-Golgi transport and at the mitochondria.
Dynamic changes in DICER levels in adipose tissue control metabolic adaptations to exercise.
Aging Promotes Mitochondria-Mediated Apoptosis in Rat Hearts.

Medicina (Kaunas). 2020 Sep 03. pii: E446. [Epub ahead of print]56(9):

Changes in Muscle Mass and Composition by Exercise and Hypoxia as Assessed by DEXA in Mice.

Benjamin D McNair, Nicholas A Marcello, Derek T Smith, Emily E Schmitt, Danielle R Bruns.

  Background and Objective: Skeletal muscle is critical for overall health and predicts quality of life in several chronic diseases, thus quantification of muscle mass and composition is necessary to understand how interventions promote changes in muscle quality. The purpose of this investigation was to quantify changes in muscle mass and composition in two distinct pre-clinical models of changes in muscle quality using a clinical dual X-ray absorptiometry (DEXA), validated for use in mice. Materials and Methods: Adult C57Bl6 male mice were given running wheels (RUN; muscle hypertrophy) or placed in hypobaric hypoxia (HH; muscle atrophy) for four weeks. Animals received weekly DEXA and terminal collection of muscle hind limb complex (HLC) and quadriceps weights and signaling for molecular regulators of muscle mass and composition. Results: HH decreased total HLC muscle mass with no changes in muscle composition. RUN induced loss of fat mass in both the quadriceps and HLC. Molecular mediators of atrophy were upregulated in HH while stimulators of muscle growth were higher in RUN. These changes in muscle mass and composition were quantified by a clinical DEXA, which we described and validated for use in pre-clinical models. Conclusions: RUN improves muscle composition while HH promotes muscle atrophy, though changes in composition in hypoxia remain unclear. Use of the widely available clinical DEXA for use in mice enhances translational research capacity to understand the mechanisms by which atrophy and hypertrophy promote skeletal muscle and overall health.

Keywords:  dual x-ray absorptiometry; exercise; hypoxia; mouse; muscle

DOI:  https://doi.org/10.3390/medicina56090446
Am J Clin Nutr. 2020 Sep 10. pii: nqaa229. [Epub ahead of print]

High-dose leucine supplementation does not prevent muscle atrophy or strength loss over 7 days of immobilization in healthy young males.

Sophie J Edwards, Benoit Smeuninx, James Mckendry, Yusuke Nishimura, Dan Luo, Ryan N Marshall, Molly Perkins, Jill Ramsay, Sophie Joanisse, Andrew Philp, Leigh Breen.

   BACKGROUND: Unavoidable periods of disuse lead to muscle atrophy and functional decline. Preventing such declines can reduce the risk of re-injury and improve recovery of normal physiological functioning.
OBJECTIVES: We aimed to determine the effectiveness of high-dose leucine supplementation on muscle morphology and strength during 7 d of unilateral lower-limb immobilization, and the role of myofibrillar (MyoPS) and mitochondrial (MitoPS) protein synthesis in disuse atrophy.
METHODS: Sixteen healthy males (mean ± SEM age: 23 ± 1 y) underwent 7 d of unilateral lower-limb immobilization, with thrice-daily leucine (LEU; n = 8) or placebo (PLA; n = 8) supplementation (15 g/d). Before and after immobilization, muscle strength and compartmental tissue composition were assessed. A primed continuous infusion of l-[ring-13C6]-phenylalanine with serial muscle biopsies was used to determine postabsorptive and postprandial (20 g milk protein) MyoPS and MitoPS, fiber morphology, markers of protein turnover, and mitochondrial function between the control leg (CTL) and the immobilized leg (IMB).
RESULTS: Leg fat-free mass was reduced in IMB (mean ± SEM: -3.6% ± 0.5%; P = 0.030) but not CTL with no difference between supplementation groups. Isometric knee extensor strength declined to a greater extent in IMB (-27.9% ± 4.4%) than in CTL (-14.3% ± 4.4%; P = 0.043) with no difference between groups. In response to 20 g milk protein, postprandial MyoPS rates were significantly lower in IMB than in CTL (-22% ± 4%; P < 0.01) in both LEU and PLA. Postabsorptive MyoPS rates did not differ between legs or groups. Postabsorptive MitoPS rates were significantly lower in IMB than in CTL (-14% ± 5%; P < 0.01) and postprandial MitoPS rates significantly declined in response to 20 g milk protein ingestion (CTL: -10% ± 8%; IMB: -15% ± 10%; P = 0.039), with no differences between legs or groups. There were no significant differences in measures of mitochondrial respiration between legs, but peroxisome proliferator-activated receptor γ coactivator 1-α and oxidative phosphorylation complex II and III were significantly lower in IMB than in CTL (P < 0.05), with no differences between groups.
CONCLUSIONS: High-dose leucine supplementation (15 g/d) does not appear to attenuate any functional declines associated with 7 d of limb immobilization in young, healthy males.This trial was registered at clinicaltrials.gov as NCT03762278.

Keywords:  amino acids; disuse; mitochondria; protein synthesis; skeletal muscle

DOI:  https://doi.org/10.1093/ajcn/nqaa229
Cell Rep. 2020 Sep 08. pii: S2211-1247(20)31114-1. [Epub ahead of print]32(10): 108125

Atf-6 Regulates Lifespan through ER-Mitochondrial Calcium Homeostasis.

Kristopher Burkewitz, Gaomin Feng, Sneha Dutta, Charlotte A Kelley, Michael Steinbaugh, Erin J Cram, William B Mair.

  Individually, dysfunction of both the endoplasmic reticulum (ER) and mitochondria has been linked to aging, but how communication between these organelles might be targeted to promote longevity is unclear. Here, we provide evidence that, in Caenorhabditis elegans, inhibition of the conserved unfolded protein response (UPRER) mediator, activating transcription factor (atf)-6, increases lifespan by modulating calcium homeostasis and signaling to mitochondria. Atf-6 loss confers longevity via downregulation of the ER calcium buffer, calreticulin. ER calcium release via the inositol triphosphate receptor (IP3R/itr-1) is required for longevity, while IP3R/itr-1 gain of function is sufficient to extend lifespan. Highlighting coordination between organelles, the mitochondrial calcium import channel mcu-1 is also required for atf-6 longevity. IP3R inhibition leads to impaired mitochondrial bioenergetics and hyperfusion, which is sufficient to suppress long life in atf-6 mutants. This study reveals the importance of organellar calcium handling as a critical output for the UPRER in determining the quality of aging.

Keywords:  InsP3R; UPR; aging; calreticulin; interorganelle communication; longevity

DOI:  https://doi.org/10.1016/j.celrep.2020.108125
FEBS J. 2020 Sep 05.

The eIF2α kinase HRI in innate immunity, proteostasis and mitochondrial stress.

Stephen E Girardin, Camille Cuziol, Dana J Philpott, Damien Arnoult.

  The integrated stress response (ISR) is an evolutionary conserved stress response pathway that leads to a global arrest in translation as well as to the expression of specific genes, such as the transcription factor ATF4, to promote cellular recovery. The central nexus of this pathway is the phosphorylation of the alpha subunit of eukaryotic translation initiation factor 2 (eIF2α) by one of the four eIF2α kinases that sense specific cellular stressors. The heme-regulated inhibitor (HRI) is one of these kinases and it was initially reported to be activated in response to heme deprivation. Nevertheless, further studies have established that cytosolic proteotoxicity, resulting from oxidative or osmotic stress, heat shock and proteasome inhibition, is the predominant trigger for HRI to induce the ISR. In this review, we present newly identified functions of HRI in innate immunity, proteostasis and mitochondrial stress. Indeed, HRI-mediated signaling defines a novel cytosolic unfolded protein response (cUPR) required for the proper formation of some innate immune signalosomes and the control of toxic protein aggregates, and this eIF2α kinase also serves as a relay for mitonuclear communication after a mitochondrial stress.

Keywords:  HRI; ISR; innate immunity; mitochondrial stress; proteostasis

DOI:  https://doi.org/10.1111/febs.15553
Front Cell Dev Biol. 2020 ;8 692

Mitochondrial Contact Sites in Inflammation-Induced Cardiovascular Disease.

Hao Liu, Xiao Liu, Haixia Zhuang, Hualin Fan, Dongxing Zhu, Yiming Xu, Pengcheng He, Jinbao Liu, Du Feng.

  The mitochondrion, the ATP-producing center, is both physically and functionally associated with almost all other organelles in the cell. Mitochondrial-associated membranes (MAMs) are involved in a variety of biological processes, such as lipid exchange, protein transport, mitochondrial fission, mitophagy, and inflammation. Several inflammation-related diseases in the cardiovascular system involve several intracellular events including mitochondrial dysfunction as well as disruption of MAMs. Therefore, an in-depth exploration of the function of MAMs will be of great significance for us to understand the initiation, progression, and clinical complications of cardiovascular disease (CVD). In this review, we summarize the recent advances in our knowledge of MAM regulation and function in CVD-related cells. We discuss the potential roles of MAMs in activating inflammation to influence the development of CVD.

Keywords:  autophagy; cardiovascular disease; inflammasome; inflammation; mitochondria; mitochondrial-associated membranes

DOI:  https://doi.org/10.3389/fcell.2020.00692
Geroscience. 2020 Sep 10.

Mitochondrial-derived peptides in aging and age-related diseases.

Su-Jeong Kim, Brendan Miller, Hiroshi Kumagai, Ana R Silverstein, Melanie Flores, Kelvin Yen.

  A decline in mitochondrial quality and activity has been associated with normal aging and correlated with the development of a wide range of age-related diseases. Here, we review the evidence that a decline in the levels of mitochondrial-derived peptides contributes to aging and age-related diseases. In particular, we discuss how mitochondrial-derived peptides, humanin and MOTS-c, contribute to specific aspects of the aging process, including cellular senescence, chronic inflammation, and cognitive decline. Genetic variations in the coding region of humanin and MOTS-c that are associated with age-related diseases are also reviewed, with particular emphasis placed on how mitochondrial variants might, in turn, regulate MDP expression and age-related phenotypes. Taken together, these observations suggest that mitochondrial-derived peptides influence or regulate a number of key aspects of aging and that strategies directed at increasing mitochondrial-derived peptide levels might have broad beneficial effects.

Keywords:  Age-related diseases; Aging; Humanin; MOTS-c; Mitochondria; Mitochondrial-derived peptides

DOI:  https://doi.org/10.1007/s11357-020-00262-5
Nature. 2020 Sep 09.

SLC25A51 is a mammalian mitochondrial NAD+ transporter.

Timothy S Luongo, Jared M Eller, Mu-Jie Lu, Marc Niere, Fabio Raith, Caroline Perry, Marc R Bornstein, Paul Oliphint, Lin Wang, Melanie R McReynolds, Marie E Migaud, Joshua D Rabinowitz, F Brad Johnson, Kai Johnsson, Mathias Ziegler, Xiaolu A Cambronne, Joseph A Baur.

Mitochondria require nicotinamide adenine dinucleotide (NAD+) in order to carry out the fundamental processes that fuel respiration and mediate cellular energy transduction. Mitochondrial NAD+ transporters have been identified in yeast and plants1,2 but their very existence is controversial in mammals3-5. Here we demonstrate that mammalian mitochondria are capable of taking up intact NAD+ and identify SLC25A51 (an essential6,7 mitochondrial protein of previously unknown function, also known as MCART1) as a mammalian mitochondrial NAD+ transporter. Loss of SLC25A51 decreases mitochondrial but not whole-cell NAD+ content, impairs mitochondrial respiration, and blocks the uptake of NAD+ into isolated mitochondria. Conversely, overexpression of SLC25A51 or a nearly identical paralog, SLC25A52, increases mitochondrial NAD+ levels and restores NAD+ uptake into yeast mitochondria lacking endogenous NAD+ transporters. Together, these findings identify SLC25A51 as the first transporter capable of importing NAD+ into mammalian mitochondria.

DOI: https://doi.org/10.1038/s41586-020-2741-7
FASEB J. 2020 Sep 05.

Differential effects of pre-exercise on cancer cachexia-induced muscle atrophy in fast- and slow-twitch muscles.

Minoru Tanaka, Ken Sugimoto, Taku Fujimoto, Keyu Xie, Toshimasa Takahashi, Hiroshi Akasaka, Yukiko Yasunobe, Yasushi Takeya, Koichi Yamamoto, Takumi Hirabayashi, Hidemi Fujino, Hiromi Rakugi.

  We hypothesized that pre-exercise may effectively prevent cancer cachexia-induced muscle atrophy in both fast- and slow-twitch muscle types. Additionally, the fast-twitch muscle may be more affected by cancer cachexia than slow-twitch muscle. This study aimed to evaluate the effects of pre-exercise on cancer cachexia-induced atrophy and on atrophy in fast- and slow-twitch muscles. Twelve male Wistar rats were randomly divided into sedentary and exercise groups, and another 24 rats were randomly divided into control, pre-exercise, cancer cachexia induced by intraperitoneal injections of ascites hepatoma AH130 cells, and pre-exercise plus cancer cachexia groups. We analyzed changes in muscle mass and in gene and protein expression levels of major regulators and indicators of muscle protein degradation and synthesis pathways, angiogenic factors, and mitochondrial function in both the plantaris and soleus muscles. Pre-exercise inhibited muscle mass loss, rescued protein synthesis, prevented capillary regression, and suppressed hypoxia in the plantaris and soleus muscles. Pre-exercise inhibited mitochondrial dysfunction differently in fast- and slow-twitch muscles. These results suggested that pre-exercise has the potential to inhibit cancer-cachexia-induced muscle atrophy in both fast- and slow-twitch muscles. Furthermore, the different progressions of cancer-cachexia-induced muscle atrophy in fast- and slow-twitch muscles are related to differences in mitochondrial function.

Keywords:  cancer cachexia; muscle atrophy; pre-exercise; protein degradation; protein synthesis

DOI:  https://doi.org/10.1096/fj.202001330R
Free Radic Biol Med. 2020 Sep 08. pii: S0891-5849(20)31238-7. [Epub ahead of print]

Redox modification of ryanodine receptor contributes to impaired Ca2+ homeostasis and exacerbates muscle atrophy under high altitude.

Akanksha Agrawal, Richa Rathor, Ravi Kumar, Geetha Suryakumar, Som Nath Singh, Bhuvnesh Kumar.

  At extreme altitude, prolonged and severe hypoxia menaces human function and survival, and also associated with profound loss of muscle mass which results into a debilitating critical illness of skeletal muscle atrophy. Hypobaric hypoxia altered redox homeostasis and impaired calcium ion handling in skeletal muscles. Dysregulated Ca2+ homeostasis and activated calpain is the prime stressor in high altitude hypoxia while the reason for subsequent abnormal release of pathological Ca2+ into cytoplasm is largely unexplored. The present study identified the redox remodeling in the Ca2+ release channel, Ryanodine Receptor (RyR1) owing to its hypernitrosylation state in skeletal muscles in chronic hypobaric hypoxia exposed rats. RyR1-hypernitrosylation decreases the binding of FKBP12/calstabin-1 and other complexes from the channel, causing "leakiness" in RyR1 ion-channel. A strong RyR1 stabilizer, S107 enhanced binding affinity of FKBP12 with hypernitrosylated RyR1, reduced Sarco(endo)plasmic reticulum (SR) Ca2+ leak and improved muscle strength and function under chronic hypoxia. Administration of S107 inhibited the skeletal muscle damage, maintained ultrastructure of sarcomere and sarcolemmal integrity. Histological analysis proved the increase in cross-sectional area of myofibers. Further, the number of apoptotic cells was also reduced by S107 treatment. Conclusively, we proposed that the redox remodeling of RyR1 (hypernitrosylated-RyR1) might be responsible for dysregulated Ca2+ homeostasis which consequently impaired muscle strength and function in response to chronic hypoxic stress. Reduced SR Ca2+ leak and enhanced binding affinity of FKBP12 may provide a novel therapeutic avenue in ameliorating skeletal muscle atrophy at high altitude.

Keywords:  Ryanodine Receptor; S107; calcium; hypobaric hypoxia; oxidative stress; skeletal muscles

DOI:  https://doi.org/10.1016/j.freeradbiomed.2020.09.001
J Inherit Metab Dis. 2020 Sep 10.

The phenotype associated with variants in TANGO2 may be explained by a dual role of the protein in ER-to-Golgi transport and at the mitochondria.

Miroslav P Milev, Djenann Saint-Dic, Khashayar Zardoui, Thomas Klopstock, Christopher Law, Felix Distelmaier, Michael Sacher.

  TANGO2 variants result in a complex disease phenotype consisting of recurrent crisis-induced rhabdomyolysis, encephalopathy, seizures, lactic acidosis, hypoglycemia, and cardiac arrhythmias. Although first described in a fruit fly model as a protein necessary for some aspect of Golgi function and organization, its role in the cell at a fundamental level has not been addressed. Such studies are necessary to better counsel families regarding treatment options and nutrition management to mitigate the metabolic aspects of the disease. The few studies performed to address the pathway(s) in which TANGO2 functions have led to enigmatic results, with some suggesting defects in membrane traffic while others suggest unknown mitochondrial defects. Here, we have performed a robust membrane trafficking assay on fibroblasts derived from three different individuals harboring TANGO2 variants and show that there is a significant delay in the movement of cargo between the endoplasmic reticulum and the Golgi. Importantly, this delay was attributed to a defect in TANGO2 function. We further show that a portion of TANGO2 protein localizes to the mitochondria through a necessary but not sufficient stretch of amino acids at the amino terminus of the protein. Fibroblasts from affected individuals also displayed changes in mitochondrial morphology. We conclude that TANGO2 functions in both membrane trafficking and in some as yet undetermined role in mitochondria physiology. The phenotype of affected individuals can be partially explained by this dual involvement of the protein. This article is protected by copyright. All rights reserved.

Keywords:  Golgi; TANGO2; cardiac arrhythmia; membrane traffic; mitochondria; rhabdomyolysis

DOI:  https://doi.org/10.1002/jimd.12312
Proc Natl Acad Sci U S A. 2020 Sep 08. pii: 202011243. [Epub ahead of print]

Dynamic changes in DICER levels in adipose tissue control metabolic adaptations to exercise.

Bruna B Brandão, Søren Madsen, Atefeh Rabiee, Matteo Oliverio, Gabriel P Ruiz, Danilo L Ferrucci, Jéssica L Branquinho, Daniela Razolli, Silas Pinto, Thomas S Nielsen, William T Festuccia, Adriano S Martins, Beatriz A Guerra, Thiago L Knittel, Ditte Søgaard, Steen Larsen, Jørn W Helge, Josef Brandauer, Lício A Velloso, Brice Emanuelli, Jan-Wilhelm Kornfeld, C Ronald Kahn, Sara G Vienberg, Juleen R Zierath, Jonas T Treebak, Marcelo A Mori.

  DICER is a key enzyme in microRNA (miRNA) biogenesis. Here we show that aerobic exercise training up-regulates DICER in adipose tissue of mice and humans. This can be mimicked by infusion of serum from exercised mice into sedentary mice and depends on AMPK-mediated signaling in both muscle and adipocytes. Adipocyte DICER is required for whole-body metabolic adaptations to aerobic exercise training, in part, by allowing controlled substrate utilization in adipose tissue, which, in turn, supports skeletal muscle function. Exercise training increases overall miRNA expression in adipose tissue, and up-regulation of miR-203-3p limits glycolysis in adipose under conditions of metabolic stress. We propose that exercise training-induced DICER-miR-203-3p up-regulation in adipocytes is a key adaptive response that coordinates signals from working muscle to promote whole-body metabolic adaptations.

Keywords:  adipose tissue; cross-talk; exercise; metabolic flexibility; microRNA

DOI:  https://doi.org/10.1073/pnas.2011243117
Life (Basel). 2020 Sep 05. pii: E178. [Epub ahead of print]10(9):

Aging Promotes Mitochondria-Mediated Apoptosis in Rat Hearts.

Mi-Hyun No, Youngju Choi, Jinkyung Cho, Jun-Won Heo, Eun-Jeong Cho, Dong-Ho Park, Ju-Hee Kang, Chang-Ju Kim, Dae Yun Seo, Jin Han, Hyo-Bum Kwak.

  Aging represents a major risk for developing cardiac disease, including heart failure. The gradual deterioration of cell quality control with aging leads to cell death, a phenomenon associated with mitochondrial dysfunction in the heart. Apoptosis is an important quality control process and a necessary phenomenon for maintaining homeostasis and normal function of the heart. However, the mechanism of mitochondria-mediated apoptosis in aged hearts remains poorly understood. Here, we used male Fischer 344 rats of various ages, representing very young (1 month), young (4 months), middle-aged (12 months), and old (20 months) rats, to determine whether mitochondria-mediated apoptotic signals and apoptosis in the left ventricle of the heart are altered notably with aging. As the rats aged, the extramyocyte space and myocyte cross-sectional area in their left ventricle muscle increased, while the number of myocytes decreased. Additionally, mitochondrion-mediated apoptotic signals and apoptosis increased remarkably during aging. Therefore, our results demonstrate that aging promotes remarkable morphological changes and increases the degree of mitochondrion-mediated apoptosis in the left ventricle of rat hearts.

Keywords:  Bcl-2 family; aging heart; mitochondria; programmed cell death

DOI:  https://doi.org/10.3390/life10090178