bims-misrem Biomed News
on Mitochondria and sarcoplasmic reticulum in muscle mass
Issue of 2020‒11‒15
eight papers selected by
Rafael Antonio Casuso Pérez
University of Granada
  1. Age-related myofiber atrophy in old mice is reversed by ten weeks voluntary high-resistance wheel running.
  2. FABP3-mediated membrane lipid saturation alters fluidity and induces ER stress in skeletal muscle with aging.
  3. Mitochondrial translation inhibition triggers ATF4 activation, leading to integrated stress response but not to mitochondria unfolded protein response.
  4. Inter-organelle membrane contact sites: implications for lipid metabolism.
  5. An Endoplasmic Reticulum ATPase Safeguards Endoplasmic Reticulum Identity by Removing Ectopically Localized Mitochondrial Proteins.
  6. TBK1-Mediated DRP1 Targeting Confers Nucleic Acid Sensing to Reprogram Mitochondrial Dynamics and Physiology.
  7. Mitochondria and nucleus cross-talk: Signaling in metabolism, apoptosis, and differentiation, and function in cancer.
  8. Is GLUT4 translocation the answer to exercise stimulated muscle glucose uptake?
  1. Exp Gerontol. 2020 Nov 09. pii: S0531-5565(20)30498-8. [Epub ahead of print] 111150
    Age-related myofiber atrophy in old mice is reversed by ten weeks voluntary high-resistance wheel running.
    Annesofie Thorup Olesen, Lasse Malchow-Møller, Rune Duus Bendixen, Michael Kjær, René Brüggebusch Svensson, Jesper Løvind Andersen, S Peter Magnusson.
      OBJECTIVE: Age-related loss of muscle mass and function can be attenuated in rodents with life-long voluntary wheel running with moderate resistance. The present study assessed if sarcopenia could be counteracted with ten weeks high intensity training.METHOD: Old (22-23 months) and middle-aged (11 months) mice were divided into three physical activity groups: Ten weeks of voluntary running in wheels with high (HR) or low resistance (LR), or no running wheel (SED). The wheel resistance was 0.5-1.5 g in the LR group and progressed from 5 g to 10 g in the HR group. Six, 8 and 5 old and 8, 9 and 9 middle-aged mice of the SED, LR and HR groups, respectively, were included in the analysis. Wheel activity was monitored throughout the intervention. Muscle mass of the tibialis anterior, gastrocnemius, soleus and plantaris muscles were measured post-mortem. Fiber type distribution and myofiber cross sectional areal (CSA) were quantified in the gastrocnemius and soleus muscles as well as total number of fibers in the soleus muscle.
    RESULTS: In the SED, the mass of all individual muscles was reduced in the old vs middle-aged (P < 0.001). In the training groups, the old mice ran significantly less, slower and for shorter bouts than the middle-aged throughout the intervention (P < 0.05). HR running increased the gastrocnemius and soleus muscle mass by 6% and 18% respectively in the old compared to SED. Fiber CSA was significantly reduced in the old SED mice, whereas fiber CSA in the old HR gastrocnemius and soleus muscles was comparable to the SED middle-aged. Fiber type shifted from 2b towards 2a in the gastrocnemius muscle of the trained old mice. HR running was more efficient than LR in maintaining muscle mass and myofiber size, and in shifting fiber types. In the middle-aged mice, similar effects were found, but less pronounced. Interestingly, fiber CSA was unaffected by running in the middle-aged.
    CONCLUSION: Ten weeks of HR running had a positive effect on muscle mass and morphology in both middle-aged and old mice. The old HR fiber CSA was greater than in old SED and comparable to the middle-aged, and the fibers shifted to a more oxidative composition (2b → 2a). Albeit less pronounced, similar training effects were observed in the middle-aged mice despite running faster and longer than the old.
    Keywords:  Aging; Exercise; Mouse model; Muscle morphology; Skeletal muscle; Training
    DOI:  https://doi.org/10.1016/j.exger.2020.111150
  2. Nat Commun. 2020 11 09. 11(1): 5661
    FABP3-mediated membrane lipid saturation alters fluidity and induces ER stress in skeletal muscle with aging.
    Seung-Min Lee, Seol Hee Lee, Youngae Jung, Younglang Lee, Jong Hyun Yoon, Jeong Yi Choi, Chae Young Hwang, Young Hoon Son, Sung Sup Park, Geum-Sook Hwang, Kwang-Pyo Lee, Ki-Sun Kwon.
      Sarcopenia is characterized by decreased skeletal muscle mass and function with age. Aged muscles have altered lipid compositions; however, the role and regulation of lipids are unknown. Here we report that FABP3 is upregulated in aged skeletal muscles, disrupting homeostasis via lipid remodeling. Lipidomic analyses reveal that FABP3 overexpression in young muscles alters the membrane lipid composition to that of aged muscle by decreasing polyunsaturated phospholipid acyl chains, while increasing sphingomyelin and lysophosphatidylcholine. FABP3-dependent membrane lipid remodeling causes ER stress via the PERK-eIF2α pathway and inhibits protein synthesis, limiting muscle recovery after immobilization. FABP3 knockdown induces a young-like lipid composition in aged muscles, reduces ER stress, and improves protein synthesis and muscle recovery. Further, FABP3 reduces membrane fluidity and knockdown increases fluidity in vitro, potentially causing ER stress. Therefore, FABP3 drives membrane lipid composition-mediated ER stress to regulate muscle homeostasis during aging and is a valuable target for sarcopenia.
    DOI:  https://doi.org/10.1038/s41467-020-19501-6
  3. Biosci Rep. 2020 Nov 09. pii: BSR20201289. [Epub ahead of print]
    Mitochondrial translation inhibition triggers ATF4 activation, leading to integrated stress response but not to mitochondria unfolded protein response.
    Katsuhiko Sasaki, Takeshi Uchiumi, Takahiro Toshima, Mikako Yagi, Yura Do, Haruka Hirai, Ko Igami, Kazuhito Gotoh, Dongchon Kang.
      Mitochondrial-nuclear communication, known as retrograde signaling, is important for regulating nuclear gene expression in response to mitochondrial dysfunction. Previously, we have found that p32/C1qbp-deficient mice, which have a mitochondrial translation defect, show ER stress response and integrated stress response (ISR) gene expression in the heart and brain. However, the mechanism by which mitochondrial translation inhibition elicits these responses is not clear. Among the transcription factors that respond to mitochondrial stress, ATF4 is a key transcription factor in the ISR. Herein, chloramphenicol, which inhibits mitochondrial DNA-encoded protein expression, induced eIF2a phosphorylation and ATF4 induction, leading to ISR gene expression. However, the expression of the mitochondrial unfolded protein response genes, which has been shown in Caenorhabditis Elegans, was not induced. Short hairpin RNA-based knockdown of ATF4 markedly inhibited the chloramphenicol-induced ISR gene expression. We also observed by ChIP analysis that induced ATF4 bound to the promoter region of several ISR genes, suggesting that mitochondrial translation inhibition induces ISR gene expression through ATF4 activation. In this study, we showed that mitochondrial translation inhibition induced the ISR through ATF4 activation rather than the mitochondrial unfolded protein response.
    Keywords:  ATF4; integratad stress responce; mitochondria; mtUPR
    DOI:  https://doi.org/10.1042/BSR20201289
  4. Biol Direct. 2020 Nov 11. 15(1): 24
    Inter-organelle membrane contact sites: implications for lipid metabolism.
    Jean E Vance.
      This article supplements a recent Perspective by Scorrano et al. in Nature Communications [10 [ (1)]:1287] in which the properties and functions of inter-organelle membrane contact sites were summarized. It is now clear that inter-organelle membrane contact sites are widespread in eukaryotic cells and that diverse pairs of organelles can be linked via unique protein tethers. An appropriate definition of what constitutes an inter-organelle membrane contact site was proposed in the Perspective. In addition, the various experimental approaches that are frequently used to study these organelle associations, as well as the advantages and disadvantages of each of these methods, were considered. The nature of the tethers that link the pairs of organelles at the contact sites was discussed in detail and some biological functions that have been ascribed to specific membrane contact sites were highlighted. Nevertheless, the functions of most types of organelle contact sites remain unclear. In the current article I have considered some of the points raised in the Perspective but have omitted detailed information on the roles of membrane contact sites in biological functions such as apoptosis, autophagy, calcium homeostasis and mitochondrial fusion. Instead, I have provided some background on the initial discovery of mitochondria-endoplasmic reticulum membrane contact sites, and have focussed on the known roles of membrane contact sites in inter-organelle lipid transport. In addition, potential roles for membrane contact sites in human diseases are briefly discussed.
    Keywords:  Cholesterol transport; Endoplasmic reticulum; Membrane contact sites; Mitochondria; Mitochondria-associated membranes (MAM); Phospholipid transport; Plasma membrane
    DOI:  https://doi.org/10.1186/s13062-020-00279-y
  5. Cell Rep. 2020 Nov 10. pii: S2211-1247(20)31352-8. [Epub ahead of print]33(6): 108363
    An Endoplasmic Reticulum ATPase Safeguards Endoplasmic Reticulum Identity by Removing Ectopically Localized Mitochondrial Proteins.
    Qing Qin, Ting Zhao, Wei Zou, Kang Shen, Xiangming Wang.
      Stringent targeting of membrane proteins to corresponding organelles is essential for organelle identity and functions. In addition to molecular pathways that target proteins to appropriate organelles, surveillance mechanisms clear mistargeted proteins from undesired destinations. Although Msp1 functions on the mitochondrial membrane to remove mistargeted proteins, the surveillance mechanism for the endoplasmic reticulum (ER) is not well understood. Here, we show that a conserved P5A-type ATPase CATP-8, which localizes to ER, removes ectopic mitochondrial tail-anchored (TA) and signal-anchored (SA) proteins from the ER. In catp-8 mutant, mitochondria fission protein FIS-1 mislocalizes to the ER membrane. Together with another mitochondria fission protein MFF-2, FIS-1 causes ER fragmentation in a Dynamin-related protein (DRP-1)-dependent manner. In addition, CATP-8 is essential for dendrite development. catp-8 mutant dramatically reduces the level of the dendrite guidance receptor DMA-1, leading to diminished dendritic arbors. Hence, P5A ATPase safeguards ER morphology and functions by preventing mitochondrial proteins mislocalization.
    DOI:  https://doi.org/10.1016/j.celrep.2020.108363
  6. Mol Cell. 2020 Oct 29. pii: S1097-2765(20)30725-5. [Epub ahead of print]
    TBK1-Mediated DRP1 Targeting Confers Nucleic Acid Sensing to Reprogram Mitochondrial Dynamics and Physiology.
    Shasha Chen, Shengduo Liu, Junxian Wang, Qirou Wu, Ailian Wang, Hongxin Guan, Qian Zhang, Dan Zhang, Xiaojian Wang, Hai Song, Jun Qin, Jian Zou, Zhengfan Jiang, Songying Ouyang, Xin-Hua Feng, Tingbo Liang, Pinglong Xu.
      Mitochondrial morphology shifts rapidly to manage cellular metabolism, organelle integrity, and cell fate. It remains unknown whether innate nucleic acid sensing, the central and general mechanisms of monitoring both microbial invasion and cellular damage, can reprogram and govern mitochondrial dynamics and function. Here, we unexpectedly observed that upon activation of RIG-I-like receptor (RLR)-MAVS signaling, TBK1 directly phosphorylated DRP1/DNM1L, which disabled DRP1, preventing its high-order oligomerization and mitochondrial fragmentation function. The TBK1-DRP1 axis was essential for assembly of large MAVS aggregates and healthy antiviral immunity and underlay nutrient-triggered mitochondrial dynamics and cell fate determination. Knockin (KI) strategies mimicking TBK1-DRP1 signaling produced dominant-negative phenotypes reminiscent of human DRP1 inborn mutations, while interrupting the TBK1-DRP1 connection compromised antiviral responses. Thus, our findings establish an unrecognized function of innate immunity governing both morphology and physiology of a major organelle, identify a lacking loop during innate RNA sensing, and report an elegant mechanism of shaping mitochondrial dynamics.
    Keywords:  DRP1; RLR-MAVS; TBK1; antiviral immunity; cell fate determination; innate immunity; mitochondrial dynamics; mitochondrion; nucleic acid sensing; phosphorylation
    DOI:  https://doi.org/10.1016/j.molcel.2020.10.018
  7. IUBMB Life. 2020 Nov 12.
    Mitochondria and nucleus cross-talk: Signaling in metabolism, apoptosis, and differentiation, and function in cancer.
    Anna Shteinfer-Kuzmine, Ankit Verma, Tasleem Arif, Or Aizenberg, Avijit Paul, Varda Shoshan-Barmaz.
      The cross-talk between the mitochondrion and the nucleus regulates cellular functions, including differentiation and adaptation to stress. Mitochondria supply metabolites for epigenetic modifications and other nuclear-associated activities and certain mitochondrial proteins were found in the nucleus. The voltage-dependent anion channel 1 (VDAC1), localized at the outer mitochondrial membrane (OMM) is a central protein in controlling energy production, cell growth, Ca2+ homeostasis, and apoptosis. To alter the cross-talk between the mitochondria and the nucleus, we used specific siRNA to silence the expression of VDAC1 in glioblastoma (GBM) U87-MG and U118-MG cell-derived tumors, and then monitored the nuclear localization of mitochondrial proteins and the methylation and acetylation of histones. Depletion of VDAC1 from tumor cells reduced metabolism, leading to inhibition of tumor growth, and several tumor-associated processes and signaling pathways linked to cancer development. In addition, we demonstrate that certain mitochondrial pro-apoptotic proteins such as caspases 3, 8, and 9, and p53 were unexpectedly overexpressed in tumors, suggesting that they possess additional non-apoptotic functions. VDAC1 depletion and metabolic reprograming altered their expression levels and subcellular localization, specifically their translocation to the nucleus. In addition, VDAC1 depletion also leads to epigenetic modifications of histone acetylation and methylation, suggesting that the interchange between metabolism and cancer signaling pathways involves mitochondria-nucleus cross-talk. The mechanisms regulating mitochondrial protein trafficking into and out of the nucleus and the role these proteins play in the nucleus remain to be elucidated.
    Keywords:  VDAC1; apoptosis; cancer; epigenetics; metabolism; mitochondria; nuclear
    DOI:  https://doi.org/10.1002/iub.2407
  8. Am J Physiol Endocrinol Metab. 2020 Nov 09.
    Is GLUT4 translocation the answer to exercise stimulated muscle glucose uptake?
    Erik A Richter.
      Exercise increases muscle glucose uptake up to 100 fold compared to rest. The magnitude of increase depends on exercise intensity and duration. While KO of GLUT4 convincingly has shown that GLUT4 is necessary for exercise to increase muscle glucose uptake, studies only show an approximate 2-fold increase in GLUT4 translocation to the muscle cell membrane when transitioning from rest to exercise. Therefore, there is a big discrepancy between the increase in glucose uptake and GLUT4 translocation. It is suggested that either the methods for measurements of GLUT4 translocation in muscle grossly underestimate the real translocation of GLUT4 or alternatively that GLUT4 intrinsic activity increases in muscle during exercise, perhaps due to increased muscle temperature and/or mechanical effects during contraction/relaxation cycles.
    Keywords:  GLUT4; GLUT4 translocation; Glucose transport; exercise; muscle glucose uptake
    DOI:  https://doi.org/10.1152/ajpendo.00503.2020
This page is being maintained by Thomas Krichel. It was last updated on 2021‒07‒23 at 10:22:09.