bims-misrem Biomed News
on Mitochondria and sarcoplasmic reticulum in muscle mass
Issue of 2021‒02‒14
thirteen papers selected by
Rafael Antonio Casuso Pérez
University of Granada


  1. Am J Physiol Cell Physiol. 2021 Feb 10.
    Qualls AE, Southern WM, Call JA.
      Skeletal muscle mitochondria are highly adaptable, highly dynamic organelles that maintain the functional integrity of the muscle fiber by providing ATP for contraction and cellular homeostasis (e.g., Na+/K+ ATPase). Emerging as early modulators of inflammation, mitochondria sense and respond to cellular stress. Mitochondria communicate with the environment, in part, by release of physical signals called mitochondrial-derived damage-associated molecular patterns (mito-DAMPs) and deviation from routine function (e.g. reduced ATP production, Ca2+ overload). When skeletal muscle is compromised, mitochondria contribute to an acute inflammatory response necessary for myofibril regeneration; however, exhaustive signaling associated with altered or reduced mitochondrial function can be detrimental to muscle outcomes. Here we describe changes in mitochondrial content, structure, and function following skeletal muscle injury and disuse and highlight the influence of mitochondrial-cytokine crosstalk on muscle regeneration and recovery. While the appropriate therapeutic modulation following muscle stressors remains unknown, retrospective gene expression analysis reveal interleukin-6 (IL-6), interleukin-1b (IL-1b), chemokine C-X-C motif ligand 1 (CXCL1), and monocyte chemoattractant protein 1 (MCP-1) are significantly upregulated following three unique muscle injuries. These cytokines modulate mitochondrial function and execute bona fide pleiotropic roles that can aid functional recovery of muscle; however, when aberrant, chronically disrupt healing partly by exacerbating mitochondrial dysfunction. Multidisciplinary efforts to delineate the opposing regulatory roles of inflammatory cytokines in the muscle-mitochondrial environment are required to modulate regenerative behavior following skeletal muscle injury or disuse. Future therapeutic directions to consider include quenching or limited release of mito-DAMPs and cytokines present in cytosol or circulation.
    Keywords:  IL-6; inflammation; mito-DAMPs; mitochondria; skeletal muscle injury
    DOI:  https://doi.org/10.1152/ajpcell.00462.2020
  2. Exp Mol Med. 2021 Feb 08.
    Bhattarai KR, Riaz TA, Kim HR, Chae HJ.
      The endoplasmic reticulum (ER) is an essential organelle of eukaryotic cells. Its main functions include protein synthesis, proper protein folding, protein modification, and the transportation of synthesized proteins. Any perturbations in ER function, such as increased demand for protein folding or the accumulation of unfolded or misfolded proteins in the ER lumen, lead to a stress response called the unfolded protein response (UPR). The primary aim of the UPR is to restore cellular homeostasis; however, it triggers apoptotic signaling during prolonged stress. The core mechanisms of the ER stress response, the failure to respond to cellular stress, and the final fate of the cell are not yet clear. Here, we discuss cellular fate during ER stress, cross talk between the ER and mitochondria and its significance, and conditions that can trigger ER stress response failure. We also describe how the redox environment affects the ER stress response, and vice versa, and the aftermath of the ER stress response, integrating a discussion on redox imbalance-induced ER stress response failure progressing to cell death and dynamic pathophysiological changes.
    DOI:  https://doi.org/10.1038/s12276-021-00560-8
  3. Front Cell Dev Biol. 2020 ;8 609493
    Angebault C, Panel M, Lacôte M, Rieusset J, Lacampagne A, Fauconnier J.
      Besides skeletal muscle dysfunction, Duchenne muscular dystrophy (DMD) exhibits a progressive cardiomyopathy characterized by an impaired calcium (Ca2+) homeostasis and a mitochondrial dysfunction. Here we aimed to determine whether sarco-endoplasmic reticulum (SR/ER)-mitochondria interactions and mitochondrial function were impaired in dystrophic heart at the early stage of the pathology. For this purpose, ventricular cardiomyocytes and mitochondria were isolated from 3-month-old dystrophin-deficient mice (mdx mice). The number of contacts points between the SR/ER Ca2+ release channels (IP3R1) and the porine of the outer membrane of the mitochondria, VDAC1, measured using in situ proximity ligation assay, was greater in mdx cardiomyocytes. Expression levels of IP3R1 as well as the mitochondrial Ca2+ uniporter (MCU) and its regulated subunit, MICU1, were also increased in mdx heart. MICU2 expression was however unchanged. Furthermore, the mitochondrial Ca2+ uptake kinetics and the mitochondrial Ca2+ content were significantly increased. Meanwhile, the Ca2+-dependent pyruvate dehydrogenase phosphorylation was reduced, and its activity significantly increased. In Ca2+-free conditions, pyruvate-driven complex I respiration was decreased whereas in the presence of Ca2+, complex I-mediated respiration was boosted. Further, impaired complex I-mediated respiration was independent of its intrinsic activity or expression, which remains unchanged but is accompanied by an increase in mitochondrial reactive oxygen species production. Finally, mdx mice were treated with the complex I modulator metformin for 1 month. Metformin normalized the SR/ER-mitochondria interaction, decreased MICU1 expression and mitochondrial Ca2+ content, and enhanced complex I-driven respiration. In summary, before any sign of dilated cardiomyopathy, the DMD heart displays an aberrant SR/ER-mitochondria coupling with an increase mitochondrial Ca2+ homeostasis and a complex I dysfunction. Such remodeling could be reversed by metformin providing a novel therapeutic perspective in DMD.
    Keywords:  Duchenne muscular dystrophy cardiomyopathy; MICU1; calcium; mitochondria-associated ER membrane; mitochondrial calcium uniporter
    DOI:  https://doi.org/10.3389/fcell.2020.609493
  4. Acta Physiol (Oxf). 2021 Feb 11. e13625
    Jacobs RA, Lundby C.
      AIM: This study sought to provide a statistically robust reference for measures of mitochondrial function from standardized high-resolution respirometry with permeabilized human skeletal muscle (ex vivo), compare analogous values obtained via indirect calorimetry, arterial-venous O2 differences, and 31 P magnetic resonance spectroscopy (in vivo), and attempt to resolve differences across complementary methodologies as necessary.METHODS: Data derived from 831 study participants across research published throughout March 2009 to November 2019 was amassed to examine the biological relevance of ex vivo assessments under standard conditions, i.e. physiological temperatures of 37 °C and respiratory chamber oxygen concentrations of ~250-500 μM.
    RESULTS: Standard ex vivo-derived measures are lower (Z ≥ 3.01, p ≤ 0.0258) en masse than corresponding in vivo-derived values. Correcting respiratory values to account for mitochondrial temperatures 10 °C higher than skeletal muscle temperatures at maximal exercise (~ 50 °C): i.) transforms data to resemble (Z ≤ 0.8, p > 0.9999) analogous yet context-specific in vivo measures, e.g. data collected during maximal 1-leg knee extension exercise; and ii.) supports the position that maximal skeletal muscle respiratory rates exceed (Z ≥ 13.2, p < 0.0001) those achieved during maximal whole-body exercise, e.g. maximal cycling efforts.
    CONCLUSION: This study outlines and demonstrates necessary considerations when actualizing the biological relevance of human skeletal muscle respiratory control, metabolic flexibility, and bioenergetics from standard ex vivo-derived assessments using permeabilized human muscle. These findings detail how cross-procedural comparisons of human skeletal muscle mitochondrial function may be collectively scrutinized in their relationship to human health and lifespan.
    Keywords:  carbohydrate oxidation rates; fatty acid oxidation rates; human bioenergetics; metabolic flexibility; skeletal muscle mitochondria; skeletal muscle temperature
    DOI:  https://doi.org/10.1111/apha.13625
  5. Nat Commun. 2021 02 10. 12(1): 929
    Steimle S, van Eeuwen T, Ozturk Y, Kim HJ, Braitbard M, Selamoglu N, Garcia BA, Schneidman-Duhovny D, Murakami K, Daldal F.
      Respiratory electron transport complexes are organized as individual entities or combined as large supercomplexes (SC). Gram-negative bacteria deploy a mitochondrial-like cytochrome (cyt) bc1 (Complex III, CIII2), and may have specific cbb3-type cyt c oxidases (Complex IV, CIV) instead of the canonical aa3-type CIV. Electron transfer between these complexes is mediated by soluble (c2) and membrane-anchored (cy) cyts. Here, we report the structure of an engineered bc1-cbb3 type SC (CIII2CIV, 5.2 Å resolution) and three conformers of native CIII2 (3.3 Å resolution). The SC is active in vivo and in vitro, contains all catalytic subunits and cofactors, and two extra transmembrane helices attributed to cyt cy and the assembly factor CcoH. The cyt cy is integral to SC, its cyt domain is mobile and it conveys electrons to CIV differently than cyt c2. The successful production of a native-like functional SC and determination of its structure illustrate the characteristics of membrane-confined and membrane-external respiratory electron transport pathways in Gram-negative bacteria.
    DOI:  https://doi.org/10.1038/s41467-021-21051-4
  6. J Physiol. 2021 Feb 12.
    Bartlett MF, Fitzgerald LF, Kent JA.
      NEW FINDINGS: The oxygen cost of high-intensity exercise at power outputs above an individual's lactate threshold (LT) is greater than would be predicted by the linear oxygen consumption-power relationship observed below the LT. However, whether these augmentations are caused by an increased ATP cost of force generation (ATPCOST ) or an increased oxygen cost of ATP synthesis is unclear. We used 31 P-MRS to measure changes in cytosolic [ADP] (intramyocellular marker of oxidative metabolism), oxidative ATP synthesis (ATPOX ), and ATPCOST during a 6-stage, stepwise knee extension protocol. ATPCOST was unchanged across stages. The relationship between [ADP] and muscle power output was augmented at workloads above the pH threshold (pHT ; proxy for LT), whereas increases in ATPOX were attenuated. These results suggest the greater oxygen cost of contractions at workloads beyond the pHT is not caused by mechanisms that increase ATPCOST , but rather mechanisms that alter intrinsic mitochondrial function or capacity.ABSTRACT: Increases in skeletal muscle metabolism and oxygen consumption are linearly related to muscle power output for workloads below the lactate threshold (LT), but are augmented (i.e., greater rate of increase relative to workload) thereafter. Presently, it is unclear whether these metabolic augmentations are caused by increases in the ATP cost of force generation (ATPCOST ) or changes in the efficiency of mitochondrial oxygen consumption and oxidative ATP synthesis (ATPOX ). To partition these two hypotheses in vivo, we used 31 P-MRS to calculate slopes relating step-changes in muscle work to concurrent changes in cytosolic phosphates and ATPOX before and after the pH threshold (pHT ; used here as a proxy for LT) within the vastus lateralis muscle of eight young adults during a stepwise knee extension test. Changes in muscle phosphates and ATPOX were linearly related to workload above and below the pHT . However, slopes above the pHT were greater for muscle phosphates (p<0.05) and lower for ATPOX (p<0.05) than were the slopes observed below the pHT . The maximal capacity for ATPOX (Vmax ) and ADP-specific ATPOX also declined beyond the pHT (p<0.05), whereas ATPCOST was unchanged (p = 0.10). These results oppose the hypothesis that high-intensity contractions increase ATPCOST and suggest that greater oxidative metabolism at workloads beyond the pHT is caused by mechanisms that affect intrinsic mitochondrial function or capacity, such as alterations in substrate selection or electron entry into the electron transport chain, temperature-mediated changes in mitochondrial permeability to protons, or stimulation of mitochondrial uncoupling by reactive oxygen species generation. This article is protected by copyright. All rights reserved.
    Keywords:  ATP cost; VO2 slow component; bioenergetics; metabolism; mitochondria; muscle; muscle fatigue; oxidative phosphorylation; uncoupling
    DOI:  https://doi.org/10.1113/JP280851
  7. Free Radic Biol Med. 2021 Feb 04. pii: S0891-5849(21)00072-1. [Epub ahead of print]
    Villalba JM, Navas P.
      Coenzyme Q (CoQ, ubiquinone/ubiquinol) is a ubiquitous and unique molecule that drives electrons in mitochondrial respiratory chain and an obligatory step for multiple metabolic pathways in aerobic metabolism. Alteration of CoQ biosynthesis or its redox stage are causing mitochondrial dysfunctions as hallmark of heterogeneous disorders as mitochondrial/metabolic, cardiovascular, and age-associated diseases. Regulation of CoQ biosynthesis pathway is demonstrated to affect all steps of proteins production of this pathway, posttranslational modifications and protein-protein-lipid interactions inside mitochondria. There is a bi-directional relationship between CoQ and the epigenome in which not only the CoQ status determines the epigenetic regulation of many genes, but CoQ biosynthesis is also a target for epigenetic regulation, which adds another layer of complexity to the many pathways by which CoQ levels are regulated by environmental and developmental signals to fulfill its functions in eukaryotic aerobic metabolism.
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2021.01.055
  8. Front Immunol. 2020 ;11 611347
    Smith JA.
      The anti-viral pattern recognition receptor STING and its partnering cytosolic DNA sensor cGAS have been increasingly recognized to respond to self DNA in multiple pathologic settings including cancer and autoimmune disease. Endogenous DNA sources that trigger STING include damaged nuclear DNA in micronuclei and mitochondrial DNA (mtDNA). STING resides in the endoplasmic reticulum (ER), and particularly in the ER-mitochondria associated membranes. This unique location renders STING well poised to respond to intracellular organelle stress. Whereas the pathways linking mtDNA and STING have been addressed recently, the mechanisms governing ER stress and STING interaction remain more opaque. The ER and mitochondria share a close anatomic and functional relationship, with mutual production of, and inter-organelle communication via calcium and reactive oxygen species (ROS). This interdependent relationship has potential to both generate the essential ligands for STING activation and to regulate its activity. Herein, we review the interactions between STING and mitochondria, STING and ER, ER and mitochondria (vis-à-vis calcium and ROS), and the evidence for 3-way communication.
    Keywords:  STING; cGAS; endoplasmic reticulum; mitochondria; reactive oxygen species; unfolded protein response
    DOI:  https://doi.org/10.3389/fimmu.2020.611347
  9. Biochim Biophys Acta Mol Basis Dis. 2021 Feb 05. pii: S0925-4439(21)00032-6. [Epub ahead of print] 166099
    Lee JM, Park S, Lee D, Ginting RP, Lee MR, Lee MW, Han J.
      Endoplasmic reticulum (ER) stress is closely associated with various metabolic diseases, such as obesity and diabetes. Development of beige/brite adipocytes increases thermogenesis and helps to reduce obesity. Although the relationship between ER stress and white adipocytes has been studied considerably, the possible role of ER stress and the unfolded protein response (UPR) induction in beige adipocytes differentiation remain to be investigated. In this study we investigated how ER stress affected beige adipocytes differentiation both in vitro and in vivo. Phosphorylation of eIF2α was transiently decreased in the early phase (day 2), whereas it was induced at the late phase with concomitant induction of C/EBP homologous protein (CHOP) during beige adipocytes differentiation. Forced expression of CHOP inhibited the expression of beige adipocytes markers, including Ucp1, Cox8b, Cidea, Prdm16, and Pgc-1α, following the induction of beige adipocytes differentiation. When ER stress was reduced by the chemical chaperone tauroursodeoxycholic acid (TUDCA), the expression of the beige adipocytes marker uncoupling protein 1 (UCP1) was significantly enhanced in inguinal white adipose tissue (iWAT) and high fat diet (HFD)-induced abnormal metabolic phenotype was improved. In summary, we found that ER stress and the UPR induction were closely involved in beige adipogenesis. These results suggest that modulating ER stress could be a potential therapeutic intervention against metabolic dysfunctions via activation of iWAT browning.
    Keywords:  Adipocyte; Browning; C/EBP homologous protein; Endoplasmic reticulum; TUDCA; UCP1
    DOI:  https://doi.org/10.1016/j.bbadis.2021.166099
  10. EMBO Rep. 2021 Feb 08. e50629
    Liu L, Li Y, Wang J, Zhang D, Wu H, Li W, Wei H, Ta N, Fan Y, Liu Y, Wang X, Wang J, Pan X, Liao X, Zhu Y, Chen Q.
      Mitophagy is an essential cellular autophagic process that selectively removes superfluous and damaged mitochondria, and it is coordinated with mitochondrial biogenesis to fine tune the quantity and quality of mitochondria. Coordination between these two opposing processes to maintain the functional mitochondrial network is of paramount importance for normal cellular and organismal metabolism. However, the underlying mechanism is not completely understood. Here we report that PGC-1α and nuclear respiratory factor 1 (NRF1), master regulators of mitochondrial biogenesis and metabolic adaptation, also transcriptionally upregulate the gene encoding FUNDC1, a previously characterized mitophagy receptor, in response to cold stress in brown fat tissue. NRF1 binds to the classic consensus site in the promoter of Fundc1 to upregulate its expression and to enhance mitophagy through its interaction with LC3. Specific knockout of Fundc1 in BAT results in reduced mitochondrial turnover and accumulation of functionally compromised mitochondria, leading to impaired adaptive thermogenesis. Our results demonstrate that FUNDC1-dependent mitophagy is directly coupled with mitochondrial biogenesis through the PGC-1α/NRF1 pathway, which dictates mitochondrial quantity, quality, and turnover and contributes to adaptive thermogenesis.
    Keywords:  adaptive thermogenesis; brown adipose tissue; mitochondrial biogenesis; mitophagy
    DOI:  https://doi.org/10.15252/embr.202050629
  11. Cell Calcium. 2021 Jan 02. pii: S0143-4160(20)30186-X. [Epub ahead of print]94 102344
    Antonucci S, Di Lisa F, Kaludercic N.
      Mitochondrial reactive oxygen species (mROS) are routinely produced at several sites within the organelle. The balance in their formation and elimination is maintained by a complex and robust antioxidant system. mROS may act as second messengers and regulate a number of physiological processes, such as insulin signaling, cell differentiation and proliferation, wound healing, etc. Nevertheless, when a sudden or sustained increase in ROS formation is not efficiently neutralized by the endogenous antioxidant defense system, the detrimental impact of high mROS levels on cell function and viability eventually results in disease development. In this review, we will focus on the dual role of mROS in pathophysiology, emphasizing the physiological role exerted by a regulated mROS production/elimination, and discussing the detrimental effects evoked by an imbalance in mitochondrial redox state. Furthermore, we will touch upon the interplay between mROS and Ca2+ homeostasis.
    Keywords:  Calcium; Mitochondria; Oxidative stress; Reactive oxygen species
    DOI:  https://doi.org/10.1016/j.ceca.2020.102344
  12. Autophagy. 2021 Feb 08.
    You JS, Chen J.
      Macroautophagy/autophagy plays a critical role in restoring/maintaining skeletal muscle function under normal conditions as well as during damage-induced regeneration. This homeostatic degradation mechanism, however, rapidly declines with aging leading to functional deterioration of skeletal muscles. ARHGEF3 is a RHOA- and RHOB-specific GEF capable of inhibiting myogenic AKT signaling independently of its GEF function. Our recent study reveals that ARHGEF3 negatively regulates skeletal muscle autophagy during injury-induced regeneration and normal aging. By enhancing autophagy, arhgef3 knockout augments the regenerative capacity of muscles in both young and regeneration-defective middle-aged mice and prevents age-related loss of muscle strength. We further show that the GEF activity of ARHGEF3 toward ROCK, but not its downstream target AKT, mediates its function in muscle regeneration. These findings suggest that ARHGEF3 may be a candidate therapeutic target for impaired muscle regeneration, age-related muscle weakness, and potentially other diseases arising from aberrant regulation of autophagy.
    Keywords:  AKT; ARHGEF3; Aging; RHOA; ROCK; autophagy; injury; regeneration; skeletal muscle; strength
    DOI:  https://doi.org/10.1080/15548627.2021.1886721