bims-misrem Biomed News
on Mitochondria and sarcoplasmic reticulum in muscle mass
Issue of 2020‒12‒20
seven papers selected by
Rafael Antonio Casuso Pérez
University of Granada


  1. Acta Physiol (Oxf). 2020 Dec 12. e13599
    Snijders T, Holwerda AM, van Loon LJC, Verdijk LB.
      AIM: To assess the relation between muscle fiber hypertrophy and myonuclear accretion in relatively small and large muscle fiber size clusters following prolonged resistance exercise training in older adults.METHODS: Muscle biopsies were collected before and after 12 weeks of resistance exercise training in 40 healthy, older men (70 ± 3 y). All muscle fibers were ordered by size and categorized in four muscle fiber size clusters: 'Small': 2000-3999 µm2 , 'Moderate': 4000-5999 µm2 , 'Large': 6000-7999 µm2 and 'Largest': 8000-9999 µm2 . Changes in muscle fiber size cluster distribution were related to changes in muscle fiber size, myonuclear content, and myonuclear domain size.
    RESULTS: With training, the percentage of muscle fibers decreased in the Small (from 23 ± 12 to 17 ± 14%, P < 0.01) and increased in the Largest (from 11 ± 8 to 15 ± 10%, P < 0.01) muscle fiber size clusters. The decline in the percentage of Small muscle fibers was accompanied by an increase in overall myonuclear domain size (r = -0.466, P = 0.002) and myonuclear content (r = -0.390, P = 0.013). In contrast, the increase in the percentage of the Largest muscle fibers was accompanied by an overall increase in myonuclear content (r = 0.616, P < 0.001), but not in domain size.
    CONCLUSION: Prolonged resistance-type exercise training induces a decline in the percentage of small as well as an increase in the percentage of the largest muscle fibers in older adults. Whereas the change in the percentage of small fibers is best predicted by an increase in overall myonuclear domain size, the change in the percentage of the largest fibers is associated with an overall increase in myonuclear content.
    Keywords:  Myonuclear domain size; growth; human; hypertrophy; muscle
    DOI:  https://doi.org/10.1111/apha.13599
  2. Front Endocrinol (Lausanne). 2020 ;11 592129
    Cheng H, Gang X, He G, Liu Y, Wang Y, Zhao X, Wang G.
      Mitochondria and the endoplasmic reticulum (ER) are connected at multiple sites via what are known as mitochondria-associated ER membranes (MAMs). These associations are known to play an important role in maintaining cellular homeostasis. Impaired MAM signaling has wide-ranging effects in many diseases, such as obesity, diabetes, and neurodegenerative disorders. Accumulating evidence has suggested that MAMs influence insulin signaling through different pathways, including those associated with Ca2+ signaling, lipid metabolism, mitochondrial function, ER stress responses, and inflammation. Altered MAM signaling is a common feature of insulin resistance in different tissues, including the liver, muscle, and even the brain. In the liver, MAMs are key glucose-sensing regulators and have been proposed to be a hub for insulin signaling. Impaired MAM integrity has been reported to disrupt hepatic responses to changes in glucose availability during nutritional transition and to induce hepatic insulin resistance. Meanwhile, these effects can be rescued by the reinforcement of MAM interactions. In contrast, several studies have proposed that enhanced ER-mitochondria connections are detrimental to hepatic insulin signaling and can lead to mitochondrial dysfunction. Thus, given these contradictory results, the role played by the MAM in the regulation of hepatic insulin signaling remains elusive. Similarly, in skeletal muscle, enhanced MAM formation may be beneficial in the early stage of diabetes, whereas continuous MAM enhancement aggravates insulin resistance. Furthermore, recent studies have suggested that ER stress may be the primary pathway through which MAMs induce brain insulin resistance, especially in the hypothalamus. This review will discuss the possible mechanisms underlying MAM-associated insulin resistance as well as the therapeutic potential of targeting the MAM in the treatment of type 2 diabetes.
    Keywords:  endoplasmic reticulum; endoplasmic reticulum stress; insulin resistance; mitochondria; mitochondria-associated endoplasmic reticulum membrane; type 2 diabetes
    DOI:  https://doi.org/10.3389/fendo.2020.592129
  3. Front Cell Dev Biol. 2020 ;8 594416
    van der Rijt S, Molenaars M, McIntyre RL, Janssens GE, Houtkooper RH.
      Since the identification and definition of the hallmarks of aging, these aspects of molecular and cellular decline have been most often described as isolated or distinct mechanisms. However, there is significant evidence demonstrating interplay between most of these hallmarks and that they have the capacity to influence and regulate one another. These interactions are demonstrable across the tree of life, yet not all aspects are conserved. Here, we describe an integrative view on the hallmarks of aging by using the hallmark "mitochondrial dysfunction" as a focus point, and illustrate its capacity to both influence and be influenced by the other hallmarks of aging. We discuss the effects of mitochondrial pathways involved in aging, such as oxidative phosphorylation, mitochondrial dynamics, mitochondrial protein synthesis, mitophagy, reactive oxygen species and mitochondrial DNA damage in relation to each of the primary, antagonistic and integrative hallmarks. We discuss the similarities and differences in these interactions throughout the tree of life, and speculate how speciation may play a role in the variation in these mechanisms. We propose that the hallmarks are critically intertwined, and that mapping the full extent of these interactions would be of significant benefit to the aging research community.
    Keywords:  aging; hallmarks of aging; interplay; mitochondria; tree of life
    DOI:  https://doi.org/10.3389/fcell.2020.594416
  4. Redox Biol. 2020 Dec 01. pii: S2213-2317(20)31029-6. [Epub ahead of print]38 101824
    Ren D, He Z, Fedorova J, Zhang J, Wood E, Zhang X, Kang DE, Li J.
      Sestrin2 (Sesn2) is a stress-inducible protein that declines with aging in the heart. We reported that rescue Sesn2 levels in aged mouse hearts through gene therapy improves the resistance of aged hearts to ischemia and reperfusion (I/R) insults. We hypothesize that Sesn2 as a scaffold protein maintains mitochondrial integrity to protect heart from ischemic injury during I/R. Young C57BL/6 J (3-6 months), aged C57BL/6 J (24-26 months), and young Sesn2 KO (3-6 months, C57BL/6 J background) mice were subjected to in vivo regional ischemia and reperfusion. The left ventricle was collected for transcriptomics, proteomics and metabolomics analysis. The results demonstrated that Sesn2 deficiency leads to aging-like cardiac diastolic dysfunction and intolerance to ischemia reperfusion stress. Seahorse analysis demonstrated that Sesn2 deficiency in aged and young Sesn2 KO versus young hearts lead to impaired mitochondrial respiration rate with defects in Complex I and Complex II activity. The Sesn2 targeted proteomics analysis revealed that Sesn2 plays a critical role in maintaining mitochondrial functional integrity through modulating mitochondria biosynthesis and assembling of oxidative phosphorylation (OXPHOS) complexes. The RNA-Seq data showed that alterations in the expression of mitochondrial compositional and functional genes and substrate metabolism related genes in young Sesn2 KO and aged versus young hearts. Further immunofluorescence and immunoprecipitation analysis demonstrated that Sesn2 is translocated into mitochondria and interacts with OXPHOS components to maintain mitochondrial integrity in response to I/R stress. Biochemical analysis revealed that Sesn2 is associated with citrate cycle components to modulate pyruvate dehydrogenase and isocitrate dehydrogenase activities during I/R stress. Thus, Sesn2 serves as a scaffold protein interacting with OXPHOS components to maintain mitochondrial integrity under I/R stress. Age-related downregulation of cardiac Sesn2 fragilizes mitochondrial functional integrity in response to ischemic stress.
    Keywords:  Aging; Ischemia reperfusion injury; Metabolism; Mitochondria; Sestrin2
    DOI:  https://doi.org/10.1016/j.redox.2020.101824
  5. Curr Protoc Cell Biol. 2020 Dec;89(1): e116
    Osto C, Benador IY, Ngo J, Liesa M, Stiles L, Acin-Perez R, Shirihai OS.
      Measuring oxygen consumption allows for the role of mitochondrial function in biological phenomena and mitochondrial diseases to be determined. Although respirometry has become a common approach in disease research, current methods are limited by the necessity to process and measure tissue samples within 1 hr of acquisition. Detailed by Acin-Perez and colleagues, a new respirometry approach designed for previously frozen tissue samples eliminates these hurdles for mitochondrial study. This technique allows for the measurement of maximal respiratory capacity in samples frozen for long-term storage before testing. This protocol article describes the optimal tissue isolation methods and the combination of substrates to define electron transport chain function at high resolution in previously frozen tissue samples. © 2020 The Authors. Basic Protocol 1: Sample collection, storage, and homogenization for previously frozen tissue respirometry Basic Protocol 2: Running a Seahorse respirometry assay using previously frozen tissue samples Basic Protocol 3: Normalization to mitochondrial content for previously frozen tissue respirometry.
    Keywords:  OCR; frozen; mitochondria; respirometry
    DOI:  https://doi.org/10.1002/cpcb.116
  6. Cell Metab. 2020 Dec 08. pii: S1550-4131(20)30653-7. [Epub ahead of print]
    Xu W, Che Y, Zhang Q, Huang H, Ding C, Wang Y, Wang G, Cao L, Hao H.
      Caspase-4 is an intracellular sensor for cytosolic bacterial lipopolysaccharide (LPS) and underlies infection-elicited pyroptosis. It is unclear whether and how caspase-4 detects host-derived factors to trigger pyroptosis. Here we show that mitochondrial permeability transition (MPT) activates caspase-4 by promoting the assembly of a protein complex, which we term the Apaf-1 pyroptosome, for the execution of facilitated pyroptosis. MPT, when induced by bile acids, calcium overload, or an adenine nucleotide translocator 1 (ANT1) activator, triggers assembly of the pyroptosome comprised of Apaf-1 and caspase-4 with a stoichiometry ratio of 7:2. Unlike the direct cleavage of gasdermin D (GSDMD) by caspase-4 upon LPS ligation, caspase-4 activated in the Apaf-1 pyroptosome proceeds to cleave caspase-3 and thereby GSDME to induce pyroptosis. Caspase-4-initiated and GSDME-executed pyroptosis underlies cholestatic liver failure. These findings identify Apaf-1 pyroptosome as a pivotal machinery for cells sensing MPT signals and may shed light on understanding how cells execute intrinsic pyroptosis under sterile conditions.
    Keywords:  Apaf-1; Caspase-4; bile acid; gasdermin E; mitochondrial permeability transition; pyroptosis
    DOI:  https://doi.org/10.1016/j.cmet.2020.11.018
  7. Int J Mol Sci. 2020 Dec 16. pii: E9587. [Epub ahead of print]21(24):
    Sun Y, Ding S.
      The endoplasmic reticulum (ER) makes physical contacts with mitochondria at specific sites, and the hubs between the two organelles are called mitochondria-associated ER membranes (MAMs). MAMs are known to play key roles in biological processes, such as intracellular Ca2+ regulation, lipid trafficking, and metabolism, as well as cell death, etc. Studies demonstrated that dysregulation of MAMs significantly contributed to insulin resistance. Alterations of MAMs' juxtaposition and integrity, impaired expressions of insulin signaling molecules, disruption of Ca2+ homeostasis, and compromised metabolic flexibility are all actively involved in the above processes. In addition, exercise training is considered as an effective stimulus to ameliorate insulin resistance. Although the underlying mechanisms for exercise-induced improvement in insulin resistance are not fully understood, MAMs may be critical for the beneficial effects of exercise.
    Keywords:  MAMs; diabetes; exercise; insulin resistance; obesity
    DOI:  https://doi.org/10.3390/ijms21249587