bims-misrem Biomed News
on Mitochondria and sarcoplasmic reticulum in muscle mass
Issue of 2020‒06‒28
nine papers selected by
Rafael Antonio Casuso Pérez
University of Granada

  1. Cell Stress Chaperones. 2020 Jun 22.
    Anand RS, Ganesan D, Rajasekaran S, Jayavelu T.
      Structures of cellular organelles are intertwined with their functions that undergo alterations once the organelles are stressed. Since organelle functions are dependent on each other, an organelle-specific stress possibly influences the structure and function of its associated organelles. In this perspective, our study demonstrated that endoplasmic reticulum (ER)-specific stress induced by tunicamycin in primary astroglial culture is associated with altered mitochondrial dynamics and matched with the changes as observed in the aging rat brain. However, the exogenous addition of biotin, a highly lipogenic and mitochondrial vitamin, ameliorates ER stress even though its direct targets are not known within ER. Alternatively, the increased biotinylation of mitochondrial carboxylases preserves its basal respiratory capacity by upregulating mitofusin 2 (Mfn2) and, possibly, its associated role on mitochondrial fusion. Furthermore, the Mfn2 increase by biotin augments physical interaction between ER and functional mitochondria to exchange biomolecules as a part of ER stress resolution. This suggests an increased demand for micronutrient biotin under ER stress resolves the same by undergoing appropriate structural and metabolic contacts between ER and mitochondria. These findings provide a paradigm to resolve stress in one organelle by sustaining the metabolic commitments of another interdependent organelle. The findings also highlight a novel role of biotin in inducing Mfn2 expression and localization under ER stress in addition to its known role as a co-enzyme.
    Keywords:  Biotin; ER stress; Mitochondrial dynamics; Mitochondrial respiration
  2. Biochim Biophys Acta Bioenerg. 2020 Jun 19. pii: S0005-2728(20)30100-6. [Epub ahead of print] 148250
    Dubinin MV, Talanov EY, Tenkov KS, Starinets VS, Mikheeva IB, Belosludtsev KN.
      Duchenne muscular dystrophy (DMD) is a progressive skeletal muscle disease that is associated with severe cardiac complications in the late stages. Significant mitochondrial dysfunction is reportedly responsible for the development of cardiomyopathy with age. At the same time, adaptive changes in mitochondrial metabolism in cardiomyocytes were identified in the early stages of DMD. In this work, we evaluate the functioning of calcium transport systems (MCU and NCLX), and MPT pore in the heart mitochondria of young dystrophin-deficient mice. As compared to wild-type animals, heart mitochondria of mdx mice have been found to be more efficient both in respect to Ca2+ uniport and Na+-dependent Ca2+ efflux. The data obtained indicate that the increased rate of Ca2+ uptake by heart mitochondria of mdx mice may be due to an increase in the ratio of MCU and MCUb subunits. In turn, an increase in the rate of Ca2+ efflux from organelles in DMD may be the result of a significant increase in the level of NCLX. Moreover, the heart mitochondria of mdx mice were more resistant to MPT pore opening, which may be due to an increase in the microviscosity of mitochondrial membranes of DMD mice. At the same time, the level of putative MPT pore proteins did not change. The paper discusses the effect of rearrangements of the mitochondrial proteome involved in the transport and accumulation of calcium on the adaptation of this organ to DMD.
    Keywords:  Ca(2+) uniporter; Duchenne muscular dystrophy; Heart; Mitochondria; Mitochondrial permeability transition; NCLX
  3. Geroscience. 2020 Jun 22.
    Zampino M, Brennan NA, Kuo PL, Spencer RG, Fishbein KW, Simonsick EM, Ferrucci L.
      Although a persistent inflammatory state has long been associated with aging and negative health outcomes, the underlying mechanisms remain unclear. Mitochondrial dysfunction has been proposed as a cause of inflammaging, but evidence of an association in humans is lacking. In this study, we analyzed the cross-sectional association between inflammatory biomarkers and mitochondrial oxidative capacity in skeletal muscle, assessed as post-exercise phosphocreatine recovery time constant by phosphorus magnetic resonance spectroscopy, in a population of 669 adults (mean age 67 years) from the Baltimore Longitudinal Study of Aging. We observed that participants with lower mitochondrial oxidative capacity exhibited hallmarks of inflammation, specifically markedly higher levels of interleukin-6 and C-reactive protein, as well as increased erythrocyte sedimentation rate when compared with participants with better oxidative capacity, independent of age and sex. We speculate that this association reflects the observation that products of damaged mitochondria, such as mitochondrial DNA, activate multiple pathways that lead to inflammation. Furthermore, excess production of oxidative species (ROS) by dysfunctional mitochondria could trigger inflammation either directly via NF-κB or through oxidative damage to proteins, lipids, and nucleic acids. Longitudinal studies are necessary to ascertain whether and through which mechanisms mitochondrial dysfunction activate inflammation or whether both these phenomena derive from a common root.
    Keywords:  Inflammaging; Mitochondria; Oxidative stress; Phosphorus magnetic resonance spectroscopy
  4. Diabetes Metab Syndr. 2020 Jun 09. pii: S1871-4021(20)30175-2. [Epub ahead of print]14(5): 867-875
    Richter-Stretton GL, Fenning AS, Vella RK.
      BACKGROUND AND AIMS: Metabolic syndrome is the concurrent presentation of multiple cardiovascular risk factors, including obesity, insulin resistance, hyperglycemia, dyslipidemia and hypertension. It has been suggested that some of these risk factors can have detrimental effects on the skeletal muscle while others can be a direct result of skeletal muscle abnormalities, showing a two-way directionality in the pathogenesis of the condition. This review aims to explore this bidirectional correlation by discussing the impact of metabolic syndrome on skeletal muscle tissue in general and will also discuss ways in which skeletal muscle alterations may contribute to the pathogenesis of metabolic syndrome.METHODS: Literature searches were conducted with key words (e.g. metabolic syndrome, skeletal muscle, hyperglycemia) using PubMed, EBSCOhost, Science Direct and Google Scholar. All article types were included in the search.
    RESULTS: The pathological mechanisms associated with metabolic syndrome, such as hyperglycemia and inflammation, have been associated with changes in skeletal muscle fiber composition, metabolism, insulin sensitivity, mitochondrial function, and strength. Additionally, some skeletal muscle alterations, particularly mitochondrial dysfunction and insulin resistance, are suggested to contribute to the development of metabolic syndrome. For example, the suggested underlying mechanisms of sarcopenia development are also contributors to metabolic syndrome pathogenesis.
    CONCLUSION: Whilst numerous studies have identified a relationship between metabolic syndrome and skeletal muscle abnormalities, further investigation into the underlying mechanisms is needed to elucidate the best prevention and management strategies for these conditions.
    Keywords:  Metabolic syndrome; Obesity; Skeletal muscle; Type 2 diabetes
  5. Biochemistry (Mosc). 2020 Jun;85(6): 651-659
    Sokolov SS, Severin FF.
      Up to now numerous studies in the field of gerontology have been published. Nevertheless, a well-known food restriction remains the most reliable and efficient way of lifespan extension. Physical activity is also a well-documented anti-aging intervention being especially efficient in slowing down the age-associated decline of skeletal muscle mass. In this review we focus on the molecular mechanisms of the effect of physical exercise on muscle tissues. We also discuss the possibilities of pharmacological extension of this effect to the rest of the tissues. During the exercise, the level of ATP decreases triggering activation of AMP-dependent protein kinase (AMPK). This kinase stimulates antioxidant potential of the cells and their mitochondrial respiratory capacity. The exercise also induces mild oxidative stress, which, in turn, mediates the stimulation via hormetic response. Furthermore, during the exercise cells generate activators of mammalian target of rapamycin (mTOR). The intracellular ATP level increases during the rest periods between exercises thus promoting mTOR activation. Therefore, regular exercise intermittently activates anti-oxidant defenses and mitochondrial biogenesis (via AMPK and the hormetic response) of the muscle tissue, as well as its proliferative potential (via mTOR), which, in turn, impedes the age-dependent muscle atrophy. Thus, the intermittent treatment with activators of (i) AMPK combined with the inducers of hormetic response and of (ii) mTOR might partly mimic the effects of physical exercise. Importantly, pharmacological activation of AMPK takes place in the absence of ATP level decrease. The use of uncouplers of respiration and oxidative phosphorylation at the phase of AMPK activation could also prevent negative consequences of the cellular hyper-energization. It is believed that the decline of both antioxidant and proliferative potentials of the cells causes the age-dependent decline of multiple tissues, rather than only the muscular one. We argue that the approach above is applicable for the majority of tissues in an organism.
  6. Mol Cell. 2020 Jun 19. pii: S1097-2765(20)30388-9. [Epub ahead of print]
    Lin Y, Li F, Huang L, Polte C, Duan H, Fang J, Sun L, Xing X, Tian G, Cheng Y, Ignatova Z, Yang X, Wolf DA.
      eIF3, a multi-subunit complex with numerous functions in canonical translation initiation, is known to interact with 40S and 60S ribosomal proteins and translation elongation factors, but a direct involvement in translation elongation has never been demonstrated. We found that eIF3 deficiency reduced early ribosomal elongation speed between codons 25 and 75 on a set of ∼2,700 mRNAs encoding proteins associated with mitochondrial and membrane functions, resulting in defective synthesis of their encoded proteins. To promote elongation, eIF3 interacts with 80S ribosomes translating the first ∼60 codons and serves to recruit protein quality-control factors, functions required for normal mitochondrial physiology. Accordingly, eIF3e+/- mice accumulate defective mitochondria in skeletal muscle and show a progressive decline in muscle strength. Hence, eIF3 interacts with 80S ribosomes to enhance, at the level of early elongation, the synthesis of proteins with membrane-associated functions, an activity that is critical for mitochondrial physiology and muscle health.
    Keywords:  eIF3; knockout mouse; mRNA translation; mitochondrial protein synthesis; muscle strength; ribosome profiling; selective ribosome profiling; translation elongation; translation initiation; translation initiation factor 3
  7. Cell Rep. 2020 Jun 23. pii: S2211-1247(20)30789-0. [Epub ahead of print]31(12): 107808
    Chapman MA, Arif M, Emanuelsson EB, Reitzner SM, Lindholm ME, Mardinoglu A, Sundberg CJ.
      To better understand the health benefits of lifelong exercise in humans, we conduct global skeletal muscle transcriptomic analyses of long-term endurance- (9 men, 9 women) and strength-trained (7 men) humans compared with age-matched untrained controls (7 men, 8 women). Transcriptomic analysis, Gene Ontology, and genome-scale metabolic modeling demonstrate changes in pathways related to the prevention of metabolic diseases, particularly with endurance training. Our data also show prominent sex differences between controls and that these differences are reduced with endurance training. Additionally, we compare our data with studies examining muscle gene expression before and after a months-long training period in individuals with metabolic diseases. This analysis reveals that training shifts gene expression in individuals with impaired metabolism to become more similar to our endurance-trained group. Overall, our data provide an extensive examination of the accumulated transcriptional changes that occur with decades-long training and identify important "exercise-responsive" genes that could attenuate metabolic disease.
    Keywords:  RNA sequencing; endurance training; exercise physiology; gene expression; genome-scale metabolic model; human subjects; resistance training; skeletal muscle; skeletal muscle metabolism; skeletal muscle transcriptomics
  8. J Cell Sci. 2020 Jun 23. pii: jcs.240374. [Epub ahead of print]
    Lee RG, Gao J, Siira SJ, Shearwood AM, Ermer JA, Hofferek V, Mathews JC, Zheng M, Reid GE, Rackham O, Filipovska A.
      The mitochondrial inner membrane contains a unique phospholipid known as cardiolipin (CL), which stabilises the protein complexes embedded in the membrane and supports its overall structure. Recent evidence indicates that the mitochondrial ribosome may associate with the inner membrane to facilitate co-translational insertion of the hydrophobic oxidative phosphorylation (OXPHOS) proteins into the inner membrane. We generated three mutant knockout cell lines for the cardiolipin biosynthesis gene Crls1 to investigate the effects of cardiolipin loss on mitochondrial protein synthesis. Reduced CL levels caused altered mitochondrial morphology and transcriptome-wide changes that were accompanied by reduced uncoordinated mitochondrial translation rates and impaired respiratory supercomplex formation. Aberrant protein synthesis was caused by impaired formation and distribution of mitochondrial ribosomes. Reduction or loss of cardiolipin resulted in divergent mitochondrial and endoplasmic reticulum stress responses. We show that cardiolipin is required to stabilise the interaction of the mitochondrial ribosome with the membrane via its association with OXA1 during active translation. This interaction facilitates insertion of newly synthesised mitochondrial proteins into the inner membrane and stabilises the respiratory supercomplexes.
    Keywords:  Mitochondrial membranes; Mitochondrial ribosomes; Protein synthesis
  9. J Physiol. 2020 Jun 26.
    McConell GK, Wadley GD, Le Plastrier K, Linden KC.
      KEY POINTS: AMP-activated protein kinase (AMPK) is considered a major regulator of skeletal muscle metabolism during exercise. However, we previously showed that although AMPK activity increases 8-10 fold during ∼120 min of exercise at ∼65% VO2 peak in untrained individuals, there is no increase in these individuals after only 10 days of exercise training (longitudinal study). In a cross-sectional study we show that there is also a lack of activation of skeletal muscle AMPK during 120 min of cycling exercise at 65% VO2 peak in endurance-trained individuals. These findings indicate that AMPK is not an important regulator of exercise metabolism during 120 min of exercise at 65% VO2 peak in endurance trained men. It is important that more energy is directed towards examining other potential regulators of exercise metabolism.ABSTRACT: AMP-activated protein kinase (AMPK) is considered a major regulator of skeletal muscle metabolism during exercise. Indeed, AMPK is activated during exercise and activation of AMPK by 5-aminoimidazole-4-carboxyamide-ribonucleoside (AICAR) increases skeletal muscle glucose uptake and fat oxidation. However, we have previously shown that although AMPK activity increases 8-10 fold during ∼120 min of exercise at ∼65% VO2 peak in untrained individuals, there is no increase in these individuals after only 10 days of exercise training (longitudinal study). In a cross-sectional study we examined whether there is also a lack of activation of skeletal muscle AMPK during 120 min of cycling exercise at 65% VO2 peak in endurance-trained individuals. Eleven untrained (UT; VO2 peak = 37.9 ± 1.8 .min-1 ) and seven endurance trained (ET; VO2 peak = 61.8 ± 0.9 .min-1 ) males completed 120 min of cycling exercise at 66 ± 1% VO2 peak (UT: 100 ± 7 watts; ET: 190 ± 6 watts). Muscle biopsies were obtained at rest and following 30 and 120 min of exercise. Muscle glycogen was significantly (P < 0.05) higher before exercise in ET and decreased similarly during exercise in the ET and UT individuals. Exercise significantly increased calculated skeletal muscle free AMP content and more so in the UT individuals. Exercise significantly (P < 0.05) increased skeletal muscle AMPK α2 activity (7-fold), AMPK α Thr172 phosphorylation (2-fold) and ACCβ Ser222 phosphorylation (2-fold) in the UT individuals but not in the ET individuals. These findings indicate that AMPK is not an important regulator of exercise metabolism during 120 min of exercise at 65% VO2 peak in endurance trained men. This article is protected by copyright. All rights reserved.