bims-misrem Biomed News
on Mitochondria and sarcoplasmic reticulum in muscle mass
Issue of 2020‒04‒26
thirteen papers selected by
Rafael Antonio Casuso Pérez
University of Granada

  1. Biogerontology. 2020 Apr 22.
    Shally A, McDonagh B.
      Medical advancements have extended human life expectancy, which is not always accompanied by an improved quality of life or healthspan. A decline in muscle mass and function is a consequence of ageing and can result in a loss of independence in elderly individuals while increasing their risk of falls. Multiple cellular pathways have been implicated in age-related muscle atrophy, including the contribution of reactive oxygen species (ROS) and disrupted redox signalling. Aberrant levels of ROS disrupts the redox environment in older muscle, potentially disrupting cellular signalling and in some cases blunting the adaptive response to exercise. Age-related muscle atrophy is associated with disrupted mitochondrial content and function, one of the hallmarks of age-related diseases. There is a critical link between abnormal ROS generation and dysfunctional mitochondrial dynamics including mitochondrial biogenesis, fusion and fission. In order to develop effective treatments or preventative strategies, it is important to gain a comprehensive understanding of the mechanistic pathways implicated in age associated loss of muscle.
    Keywords:  Exercise; Mitochondrial dynamics; Mitophagy; Redox signalling; Skeletal muscle
  2. Am J Physiol Cell Physiol. 2020 Apr 22.
    Englund DA, Murach KA, Dungan CM, Figueiredo VC, Vechetti IJ, Dupont-Versteegden EE, McCarthy JJ, Peterson CA.
      To date, studies that have aimed to investigate the role of satellite cells during adult skeletal muscle adaptation and hypertrophy have utilized a non-translational stimulus and/or have been carried out over a relatively short time frame. While it has been shown that satellite cell depletion throughout adulthood does not drive skeletal muscle loss in sedentary mice, it remains unknown how satellite cells participate in skeletal muscle adaptation to long term physical activity. The current study was designed to determine if reduced satellite cell content throughout adulthood would influence the transcriptome-wide response to physical activity and diminish the adaptive response of skeletal muscle. We administered vehicle or tamoxifen to adult Pax7-DTA mice to deplete satellite cells and assigned them to sedentary or wheel-running conditions for 13 months. Satellite cell depletion throughout adulthood reduced balance and coordination, overall running volume and the size of muscle proprioceptors (spindle fibers). Further, satellite cell participation was necessary for optimal muscle fiber hypertrophy but not adaptations in fiber type distribution in response to lifelong physical activity. Transcriptome-wide analysis of the plantaris and soleus revealed that satellite cell function is muscle type-specific; satellite cell-dependent myonuclear accretion was apparent in oxidative muscles, whereas initiation of GPCR signaling in the glycolytic plantaris may require satellite cells to induce optimal adaptations to long term physical activity. These findings suggest targeting satellite cells may be a viable strategy to preserve physical function during aging and promote muscle growth during sustained periods of physical activity.
    Keywords:  Exercise; Hypertrophy; Physical function; Satellite cell; Stem cell
  3. Antioxidants (Basel). 2020 Apr 17. pii: E329. [Epub ahead of print]9(4):
    Pacifici F, Della-Morte D, Piermarini F, Arriga R, Scioli MG, Capuani B, Pastore D, Coppola A, Rea S, Donadel G, Andreadi A, Abete P, Sconocchia G, Bellia A, Orlandi A, Lauro D.
      With the increase in average life expectancy, several individuals are affected by age-associated non-communicable chronic diseases (NCDs). The presence of NCDs, such as type 2 diabetes mellitus (T2DM), leads to the reduction in skeletal muscle mass, a pathological condition defined as sarcopenia. A key factor linking sarcopenia with cellular senescence and diabetes mellitus (DM) is oxidative stress. We previously reported as the absence of Peroxiredoxin 6 (Prdx6), an antioxidant enzyme implicated in maintaining intracellular redox homeostasis, induces an early-stage of T2DM. In the present study we sought to understand the role of Prdx6 in the crosstalk between aging and diabetic sarcopenia, by using Prdx6 knockout (Prdx6-/-) mice. Absence of Prdx6 reduced telomeres length and Sirtuin1 (SIRT1) nuclear localization. An increase in Sa-β-Gal activity and p53-p21 pro-aging pathway were also evident. An impairment in IGF-1 (Insulin-like Groth Factor-1)/Akt-1/mTOR pathway leading to a relative increase in Forkhead Box O1 (FOXO1) nuclear localization and in a decrease of muscle differentiation as per lower levels of myoblast determination protein 1 (MyoD) was observed. Muscle atrophy was also present in Prdx6-/- mice by the increase in Muscle RING finger 1 (MuRF1) levels and proteins ubiquitination associated to a reduction in muscle strength. The present study, innovatively, highlights a fundamental role of Prdx6, in the crosstalk between aging, sarcopenia, and DM.
    Keywords:  SIRT1; aging; diabetes mellitus; insulin resistance; peroxiredoxin6; sarcopenia
  4. J Cell Biol. 2020 Apr 06. pii: e201911122. [Epub ahead of print]219(4):
    Abrisch RG, Gumbin SC, Wisniewski BT, Lackner LL, Voeltz GK.
      The steady-state morphology of the mitochondrial network is maintained by a balance of constitutive fission and fusion reactions. Disruption of this steady-state morphology results in either a fragmented or elongated network, both of which are associated with altered metabolic states and disease. How the processes of fission and fusion are balanced by the cell is unclear. Here we show that mitochondrial fission and fusion are spatially coordinated at ER membrane contact sites (MCSs). Multiple measures indicate that the mitochondrial fusion machinery, Mitofusins, accumulate at ER MCSs where fusion occurs. Furthermore, fission and fusion machineries colocalize to form hotspots for membrane dynamics at ER MCSs that can persist through sequential events. Because these hotspots can undergo fission and fusion, they have the potential to quickly respond to metabolic cues. Indeed, we discover that ER MCSs define the interface between polarized and depolarized segments of mitochondria and can rescue the membrane potential of damaged mitochondria by ER-associated fusion.
  5. Biochim Biophys Acta Mol Basis Dis. 2020 Apr 16. pii: S0925-4439(20)30146-0. [Epub ahead of print] 165801
    Cortés-Rojo C, Vargas-Vargas MA, Olmos-Orizaba BE, Rodríguez-Orozco AR, Calderón-Cortés E.
      Metabolic diseases are characterized by high NADH/NAD+ ratios due to excessive electron supply, causing defective mitochondrial function and impaired sirtuin-3 (SIRT-3) activity, the latter driving to oxidative stress and altered fatty acid β-oxidation. NADH is oxidized by the complex I in the electron transport chain, thereby factors inhibiting complex I like acetylation, cardiolipin peroxidation, and glutathionylation by low GSH/GSSG ratios affects SIRT3 function by increasing the NADH/NAD+ ratio. In this review, we summarized the evidence supporting a role of the above events in the development of insulin resistance, which is relevant in the pathogenesis of obesity and diabetes. We propose that maintenance of proper NADH/NAD+ and GSH/GSSG ratios are central to ameliorate insulin resistance, as alterations in these redox couples lead to complex I dysfunction, disruption of SIRT-3 activity, ROS production and impaired β-oxidation, the latter two being key effectors of insulin resistance.
    Keywords:  Diabetes; Lipid peroxidation; Liver; Mitochondria; Obesity; Skeletal muscle
  6. EMBO Rep. 2020 Apr 23. e50071
    Cunningham CN, Rutter J.
      The metabolic compartmentalization enabled by mitochondria is key feature of many cellular processes such as energy conversion to ATP production, redox balance, and the biosynthesis of heme, urea, nucleotides, lipids, and others. For a majority of these functions, metabolites need to be transported across the impermeable inner mitochondrial membrane by dedicated carrier proteins. Here, we examine the substrates, structural features, and human health implications of four mitochondrial metabolite carrier families: the SLC25A family, the mitochondrial ABCB transporters, the mitochondrial pyruvate carrier (MPC), and the sideroflexin proteins.
    Keywords:  metabolism; metabolite carriers; mitochondria; transporters
  7. Biochim Biophys Acta Mol Basis Dis. 2020 Apr 15. pii: S0925-4439(20)30144-7. [Epub ahead of print] 165799
    Zhang R, Jiang M, Zhang J, Qiu Y, Li D, Li S, Liu J, Liu C, Fang Z, Cao F.
      Microgravity exposure results in vascular remodeling and cardiovascular dysfunction. Here, the effects of mitochondrial oxidative stress on vascular smooth muscle cells (VSMCs) in rat cerebral arteries under microgravity simulated by hindlimb unweighting (HU) was studied. Endoplasmic reticulum (ER)-resident transmembrane sensor proteins and phenotypic markers of rat cerebral VSMCs were examined. In HU rats, CHOP expression was increased gradually, and the upregulation of the PERK-eIF2α-ATF4 pathway was the most pronounced in cerebral arteries. Furthermore, PERK/p-PERK signaling, CHOP, GRP78 and reactive oxygen species were augmented by PERK overexpression but attenuated by the mitochondria-targeting antioxidant MitoTEMPO. Meanwhile, p-PI3K, p-Akt and p-mTOR protein levels in VSMCs were increased in HU rat cerebral arteries. Compared with the control, HU rats exhibited lower α-SMA, calponin, SM-MHC and caldesmon protein levels but higher OPN and elastin levels in cerebral VSMCs. The cerebral VSMC phenotype transition from a contractile to synthetic phenotype in HU rats was augmented by PERK overexpression and 740Y-P but reversed by MitoTEMPO and the ER stress inhibitors tauroursodeoxycholic acid (TUDCA) and 4-phenylbutyric acid (4-PBA). In summary, mitochondrial oxidative stress and ER stress induced by simulated microgravity contribute to phenotype transition of cerebral VSMCs through the PERK-eIF2a-ATF4-CHOP pathway in a rat model.
    Keywords:  Endoplasmic reticulum stress; Hindlimb unweighting; Mitochondria; Oxidative stress; Phenotype of vascular smooth muscle cells; Vascular remodeling
  8. Mol Metab. 2020 Apr 16. pii: S2212-8778(20)30072-7. [Epub ahead of print] 100998
    Knudsen JR, Steenberg DE, Hingst JR, Hodgson LR, Henriquez-Olguin C, Li Z, Kiens B, Richter EA, Wojtaszewski JFP, Verkade P, Jensen TE.
      OBJECTIVE: Exercise is a cornerstone in the management of skeletal muscle insulin-resistance. A well-established benefit of a single bout of exercise is increased insulin sensitivity for hours post-exercise in the previously exercised musculature. Although rodent studies suggest that the insulin-sensitization phenomenon involves enhanced insulin-stimulated GLUT4 cell surface translocation and might involve intramuscular redistribution of GLUT4, the conservation to humans is unknown.METHODS: Healthy young males underwent an insulin-sensitizing one-legged kicking exercise bout for 1 hour followed by fatigue bouts to exhaustion. Muscle biopsies were obtained 4h post-exercise before and after a 2h hyperinsulinemic-euglycemic clamp.
    RESULTS: A detailed microscopy-based analysis of GLUT4 distribution muscle specimen in 7 different myocellular compartments revealed that prior exercise increased GLUT4 localization in insulin-responsive storage vesicles and T-tubuli. Furthermore, insulin-stimulated GLUT4 localization was augmented at the sarcolemma and in the endosomal compartments.
    CONCLUSION: An intracellular redistribution of GLUT4 post-exercise is proposed as a molecular mechanism contributing to the insulin-sensitizing effect of prior exercise in human skeletal muscle.
    Keywords:  Exercise; GLUT4; insulin sensitivity; insulin-resistance; skeletal muscle
  9. Cell Metab. 2020 Apr 17. pii: S1550-4131(20)30189-3. [Epub ahead of print]
    Herkenne S, Ek O, Zamberlan M, Pellattiero A, Chergova M, Chivite I, Novotná E, Rigoni G, Fonseca TB, Samardzic D, Agnellini A, Bean C, Di Benedetto G, Tiso N, Argenton F, Viola A, Soriano ME, Giacomello M, Ziviani E, Sales G, Claret M, Graupera M, Scorrano L.
      While endothelial cell (EC) function is influenced by mitochondrial metabolism, the role of mitochondrial dynamics in angiogenesis, the formation of new blood vessels from existing vasculature, is unknown. Here we show that the inner mitochondrial membrane mitochondrial fusion protein optic atrophy 1 (OPA1) is required for angiogenesis. In response to angiogenic stimuli, OPA1 levels rapidly increase to limit nuclear factor kappa-light-chain-enhancer of activated B cell (NFκB) signaling, ultimately allowing angiogenic genes expression and angiogenesis. Endothelial Opa1 is indeed required in an NFκB-dependent pathway essential for developmental and tumor angiogenesis, impacting tumor growth and metastatization. A first-in-class small molecule-specific OPA1 inhibitor confirms that EC Opa1 can be pharmacologically targeted to curtail tumor growth. Our data identify Opa1 as a crucial component of physiological and tumor angiogenesis.
    Keywords:  NFκB; Opa1; angiogenesis; cancer; fusion-fission; lymphangiogenesis; metastasis; mitochondria; mouse; tumor; zebrafish
  10. Front Physiol. 2020 ;11 267
    Glembotski CC, Arrieta A, Blackwood EA, Stauffer WT.
      Proteostasis encompasses a homeostatic cellular network in all cells that maintains the integrity of the proteome, which is critical for optimal cellular function. The components of the proteostasis network include protein synthesis, folding, trafficking, and degradation. Cardiac myocytes have a specialized endoplasmic reticulum (ER) called the sarcoplasmic reticulum that is well known for its role in contractile calcium handling. However, less studied is the proteostasis network associated with the ER, which is of particular importance in cardiac myocytes because it ensures the integrity of proteins that are critical for cardiac contraction, e.g., ion channels, as well as proteins necessary for maintaining myocyte viability and interaction with other cell types, e.g., secreted hormones and growth factors. A major aspect of the ER proteostasis network is the ER unfolded protein response (UPR), which is initiated when misfolded proteins in the ER activate a group of three ER transmembrane proteins, one of which is the transcription factor, ATF6. Prior to studies in the heart, ATF6 had been shown in model cell lines to be primarily adaptive, exerting protective effects by inducing genes that encode ER proteins that fortify protein-folding in this organelle, thus establishing the canonical role for ATF6. Subsequent studies in isolated cardiac myocytes and in the myocardium, in vivo, have expanded roles for ATF6 beyond the canonical functions to include the induction of genes that encode proteins outside of the ER that do not have known functions that are obviously related to ER protein-folding. The identification of such non-canonical roles for ATF6, as well as findings that the gene programs induced by ATF6 differ depending on the stimulus, have piqued interest in further research on ATF6 as an adaptive effector in cardiac myocytes, underscoring the therapeutic potential of activating ATF6 in the heart. Moreover, discoveries of small molecule activators of ATF6 that adaptively affect the heart, as well as other organs, in vivo, have expanded the potential for development of ATF6-based therapeutics. This review focuses on the ATF6 arm of the ER UPR and its effects on the proteostasis network in the myocardium.
    Keywords:  ATF6; ER stress; cardiac myocyte; proteostasis; unfolded protein response
  11. Cells. 2020 Apr 15. pii: E973. [Epub ahead of print]9(4):
    Picca A, Beli R, Calvani R, Coelho-Júnior HJ, Landi F, Bernabei R, Bucci C, Guerra F, Marzetti E.
      Mitochondrial dysfunction and systemic inflammation are major factors in the development of sarcopenia, but the molecular determinants linking the two mechanisms are only partially understood. The study of extracellular vesicle (EV) trafficking may provide insights into this relationship. Circulating small EVs (sEVs) from serum of 11 older adults with physical frailty and sarcopenia (PF&S) and 10 controls were purified and characterized. Protein levels of three tetraspanins (CD9, CD63, and CD81) and selected mitochondrial markers, including adenosine triphosphate 5A (ATP5A), mitochondrial cytochrome C oxidase subunit I (MTCOI), nicotinamide adenine dinucleotide reduced form (NADH):ubiquinone oxidoreductase subunit B8 (NDUFB8), NADH:ubiquinone oxidoreductase subunit S3 (NDUFS3), succinate dehydrogenase complex iron sulfur subunit B (SDHB), and ubiquinol-cytochrome C reductase core protein 2 (UQCRC2) were quantified by Western immunoblotting. Participants with PF&S showed higher levels of circulating sEVs relative to controls. Protein levels of CD9 and CD63 were lower in the sEV fraction of PF&S older adults, while CD81 was unvaried between groups. In addition, circulating sEVs from PF&S participants had lower amounts of ATP5A, NDUFS3, and SDHB. No signal was detected for MTCOI, NDUFB8, or UQCRC2 in either participant group. Our findings indicate that, in spite of increased sEV secretion, lower amounts of mitochondrial components are discarded through EV in older adults with PF&S. In-depth analysis of EV trafficking might open new venues for biomarker discovery and treatment development for PF&S.
    Keywords:  aging; biomarkers; exosomes; mitochondrial dynamics; mitochondrial quality control; mitochondrial-derived vesicles (MDVs); mitochondrial-lysosomal axis; mitophagy
  12. Front Cell Dev Biol. 2020 ;8 221
    Wu C, Yao W, Kai W, Liu W, Wang W, Li S, Chen Y, Wu X, Wang L, Li Y, Tong J, Qian J, Zhang L, Hong Z, Yi C.
      Mitochondria are highly dynamic organelles, which can form a network in cells through fusion, fission, and tubulation. Its morphology is closely related to the function of mitochondria. The damaged mitochondria can be removed by mitophagy. However, the relationship between mitochondrial morphology and non-selective autophagy is not fully understood. We found that mitochondrial fusion machinery, not fission or tubulation machinery, is essential for energy deprivation-induced autophagy. In response to glucose starvation, deletion of mitochondrial fusion proteins severely impaired the association of Atg1/ULK1 with Atg13, and then affected the recruitment of Atg1 and other autophagic proteins to PAS (phagophore assembly site). Furthermore, the deletion of fusion proteins blocks mitochondrial respiration, the binding of Snf1-Mec1, the phosphorylation of Mec1 by Snf1, and the dissociation of Mec1 from mitochondria under prolonged starvation. We propose that mitochondrial fusion machinery regulates energy deprivation-induced autophagy through maintaining mitochondrial respiration.
    Keywords:  autophagy; fusion machinery; glucose starvation; mitochondrial morphology; mitochondrial respiration
  13. J Mol Cell Cardiol. 2020 Apr 15. pii: S0022-2828(20)30099-7. [Epub ahead of print]
    Dorn GW.
      Mitochondria have their own genomes and their own agendas. Like their primitive bacterial ancestors, mitochondria interact with their environment and organelle colleagues at their physical interfaces, the outer mitochondrial membrane. Among outer membrane proteins, mitofusins (MFN) are increasingly recognized for their roles as arbiters of mitochondria-mitochondria and mitochondria-reticular interactions. This review examines the roles of MFN1 and MFN2 in the heart and other organs as proteins that tether mitochondria to each other or to other organelles, and as mitochondrial anchoring proteins for various macromolecular complexes. The consequences of MFN-mediated tethering and anchoring on mitochondrial fusion, motility, mitophagy, and mitochondria-ER calcium cross-talk are reviewed. Pathophysiological implications are explored from the perspective of mitofusin common functioning as tethering and anchoring proteins, rather than as mediators of individual processes. Finally, some informed speculation is provided for why mouse MFN knockout studies show severe multi-system phenotypes whereas rare human diseases linked to MFN mutations are limited in scope.
    Keywords:  Metabolism; Mitochondrial dynamics; Mitochondrial fusion; Mitochondrial transport; Mitophagy