bims-misrem Biomed News
on Mitochondria and sarcoplasmic reticulum in muscle mass
Issue of 2020‒06‒21
eleven papers selected by
Rafael Antonio Casuso Pérez
University of Granada

  1. J Appl Physiol (1985). 2020 Jun 18.
    Eshima H, Siripoksup P, Mahmassani ZS, Johnson JM, Ferrara PJ, Verkerke ARP, Salcedo A, Drummond MJ, Funai K.
      Excess reactive oxygen species (ROS) induced by physical inactivity is associated with muscle atrophy and muscle weakness. However, the role of mitochondrial ROS on disuse-induced muscle atrophy is not fully understood. The purpose of this study was to utilize a genetic strategy to examine the effect of neutralizing mitochondrial ROS on disuse-induced skeletal muscle atrophy. This was accomplished by placing wildtype (WT) and mitochondrial-targeted catalase expressing (MCAT) littermate mice on 7-days of hindlimb unloading. After assessment of body weight and composition, muscles were analyzed for individual muscle mass, force generating capacity, fiber-type, cross-sectional area, and mitochondrial phenotyping including H2O2 production. Despite a successful attenuation of mitochondrial ROS, MCAT mice were not protected from muscle atrophy. No differences were observed in body composition, lean mass, individual muscle masses, force-generating capacity, and muscle fiber cross-sectional area. These data suggest that neutralizing mitochondrial ROS is insufficient to suppress disuse-induced loss of skeletal muscle mass and contractile function.
    Keywords:  Mitochondria; Oxidative stress; Reactive oxygen species; hindlimb-unloading; muscle atrophy
  2. Cells. 2020 Jun 11. pii: E1454. [Epub ahead of print]9(6):
    Leduc-Gaudet JP, Mayaki D, Reynaud O, Broering FE, Chaffer TJ, Hussain SNA, Gouspillou G.
      Sepsis elicits skeletal muscle weakness and fiber atrophy. The accumulation of injured mitochondria and depressed mitochondrial functions are considered as important triggers of sepsis-induced muscle atrophy. It is unclear whether mitochondrial dysfunctions in septic muscles are due to the inadequate activation of quality control processes. We hypothesized that overexpressing Parkin, a protein responsible for the recycling of dysfunctional mitochondria by the autophagy pathway (mitophagy), would confer protection against sepsis-induced muscle atrophy by improving mitochondrial quality and content. Parkin was overexpressed for four weeks in the limb muscles of four-week old mice using intramuscular injections of adeno-associated viruses (AAVs). The cecal ligation and perforation (CLP) procedure was used to induce sepsis. Sham operated animals were used as controls. All animals were studied for 48 h post CLP. Sepsis resulted in major body weight loss and myofiber atrophy. Parkin overexpression prevented myofiber atrophy in CLP mice. Quantitative two-dimensional transmission electron microscopy revealed that sepsis is associated with the accumulation of enlarged and complex mitochondria, an effect which was attenuated by Parkin overexpression. Parkin overexpression also prevented a sepsis-induced decrease in the content of mitochondrial subunits of NADH dehydrogenase and cytochrome C oxidase. We conclude that Parkin overexpression prevents sepsis-induced skeletal muscle atrophy, likely by improving mitochondrial quality and contents.
    Keywords:  mitochondria; mitochondrial fission; mitochondrial fusion; muscle atrophy; septicemia
  3. Life Sci. 2020 Jun 13. pii: S0024-3205(20)30715-3. [Epub ahead of print]256 117965
    Rivera-Alvarez I, Pérez-Treviño P, Chapoy-Villanueva H, Vela-Guajardo JE, Nieblas B, Garza-González S, García-Rivas G, García N.
      BACKGROUND: Several studies have proved that physical activity (PA) regulates energetic metabolism associated with mitochondrial dynamics through AMPK activation in healthy subjects. Obesity, a condition that induces oxidative stress, mitochondrial dysfunction, and low AMPK activity leads to mitochondrial fragmentation. However, few studies describe the effect of PA on mitochondrial dynamics regulation in obesity.AIM: The present study aimed to evaluate the effect of a single session of PA on mitochondrial dynamics regulation as well as its effect on mitochondrial function and organization in skeletal muscles of obese rats (Zucker fa/fa).
    MAIN METHODS: Male Zucker lean and Zucker fa/fa rats aged 12 to 13 weeks were divided into sedentary and subjected-to-PA (single session swimming) groups. Gastrocnemius muscle was dissected into isolated fibers, mitochondria, mRNA, and total proteins for their evaluation.
    KEY FINDINGS: The results showed that PA increased the Mfn-2 protein level in the lean and obese groups, whereas Drp1 levels decreased in the obese group. OMA1 protease levels increased in the lean group and decreased in the obese group. Additionally, AMPK analysis parameters (expression, protein level, and activity) did not increase in the obese group. These findings correlated with the partial restoration of mitochondrial function in the obese group, increasing the capacity to maintain the membrane potential after adding calcium as a stressor, and increasing the transversal organization level of the mitochondria analyzed in isolated fibers.
    SIGNIFICANCE: These results support the notion that obese rats subjected to PA maintain mitochondrial function through mitochondrial fusion activation by an AMPK-independent mechanism.
    Keywords:  AMPK; Metabolic syndrome; Mitochondria quality control; Mitochondrial dynamics; Oxidative stress
  4. Physiol Rep. 2020 Jun;8(12): e14416
    Vega RB, Brouwers B, Parsons SA, Stephens NA, Pino MF, Hodges A, Yi F, Yu G, Pratley RE, Smith SR, Sparks LM.
      Exercise training and physical activity are known to be associated with high mitochondrial content and oxidative capacity in skeletal muscle. Metabolic diseases including obesity and insulin resistance are associated with low mitochondrial capacity in skeletal muscle. Certain transcriptional factors such as PGC-1α are known to mediate the exercise response; however, the precise molecular mechanisms involved in the adaptation to exercise are not completely understood. We performed multiple measurements of mitochondrial capacity both in vivo and ex vivo in lean or overweight individuals before and after an 18-day aerobic exercise training regimen. These results were compared to lean, active individuals. Aerobic training in these individuals resulted in a marked increase in mitochondrial oxidative respiratory capacity without an appreciable increase in mitochondrial content. These adaptations were associated with robust transcriptome changes. This work also identifies the Tribbles pseudokinase 1, TRIB1, as a potential mediator of the exercise response in human skeletal muscle.
    Keywords:  Tribbles 1; aerobic exercise training; mitochondrial capacity; skeletal muscle
  5. J Physiol. 2020 Jun 15.
    Dulac M, Leduc-Gaudet JP, Reynaud O, Ayoub MB, Guérin A, Finkelchtein M, Hussain SN, Gouspillou G.
      KEY POINTS: The maintenance of optimal mitochondrial content and function is critical for muscle health. Mitochondrial dynamics play key roles in mitochondrial quality control, however, the exact role that mitochondrial fission plays in skeletal muscle health remains unclear. Here we report knocking down Drp1 (a protein regulating mitochondrial fission) for 4 months in adult mouse skeletal muscle resulted in severe muscle atrophy (40% to 50%). Drp1 knockdown also led to a reduction in ADP-stimulated respiration, an increase in markers of impaired autophagy and increased muscle regeneration, denervation, fibrosis and oxidative stress. Our data indicate that Drp1 is crucial for the maintenance of normal mitochondrial function and that Drp1 depletion severely impairs muscle health.ABSTRACT: Mitochondria play central roles in skeletal muscle physiology, including energy supply, regulation of energy-sensitive signalling pathways, reactive oxygen species production/signalling, calcium homeostasis and the regulation of apoptosis. The maintenance of optimal mitochondrial content and function is therefore critical for muscle cells. Mitochondria are now well known as highly dynamic organelles, able to change their morphology through fusion and fission processes. Solid experimental evidence indicates that mitochondrial dynamics play key roles in mitochondrial quality control, and alteration in the expression of proteins regulating mitochondrial dynamics have been reported in many conditions associated with muscle atrophy and wasting. However, the exact role that mitochondrial fission plays in skeletal muscle health remains unclear. To address this issue, we investigated the impact of Drp1 (a protein regulating mitochondrial fission) knockdown, obtained intramuscular injection of Adeno-Associated Virus (AAV) in adult mouse skeletal muscle. Knocking down Drp1 for 4 months resulted in very severe muscle atrophy (40% to 50%). Drp1 knockdown also led to a reduction in ADP-stimulated respiration and increases in markers of muscle regeneration, denervation, fibrosis, oxidative stress and impaired autophagy. Our findings indicate that Drp1 is essential for the maintenance of normal mitochondrial function and that Drp1 suppression severely impairs muscle health. This article is protected by copyright. All rights reserved.
    Keywords:  fibrosis; mitochondrial dynamics; mitochondrial fission; myopathic phenotype; neuromuscular junction; oxidative stress; skeletal muscle atrophy
  6. Exp Gerontol. 2020 Jun 15. pii: S0531-5565(20)30345-4. [Epub ahead of print] 110997
    Yarnall AJ, Granic A, Waite S, Hollingsworth KG, Warren C, Vincent AE, Turnbull DM, Taylor RW, Dodds RM, Sayer AA.
      INTRODUCTION: There has been little work on the relationship between sarcopenia, a progressive skeletal muscle disorder, and age-related neurodegenerative diseases such as Parkinson's disease (PD).OBJECTIVES: We aimed to determine: 1) the feasibility of characterizing skeletal muscle across a range of cognitive function in PD; 2) if muscle mitochondrial respiratory chain (MRC) function and content are preserved in older adults with PD.
    METHODS: Sarcopenia was defined using handgrip strength, chair rise and bioimpedance analysis. MRC function was assessed using phosphorous magnetic resonance spectroscopy (MRS) by estimating τ1/2 PCr (s) (phosphocreatine half-time recovery) in the calf muscles following a bout of aerobic exercise. Biopsy of the vastus lateralis muscle was performed, and MRC content assessed by fluorescent immunohistochemistry for porin and components of MRC Complexes I and IV.
    RESULTS: Nine participants (78% male; mean age 79.9; PD duration 3.3 years) were recruited. Four had cognitive impairment. Six participants had probable sarcopenia. Eight participants completed MRS and had mean (SD) τ1/2 PCr of 37.8 (7.6) seconds, suggesting preserved mitochondrial function. Muscle biopsies were obtained in all and the procedure was well tolerated. Porin Z-score, a proxy for mitochondrial mass, was lower than expected compared to controls (0-89% of fibres with low porin). There was a small amount of Complex I (0.16-4.59%) and Complex IV (0-3.79%) deficiency.
    CONCLUSIONS: Detailed phenotyping, muscle biopsy and imaging was feasible and acceptable across a spectrum of cognitive function in PD. Sarcopenia was relatively common and may be associated with lower mitochondrial mass and low levels of MRC deficiency.
    Keywords:  Aging; Cognition; Mitochondrial function; Parkinson's disease; Sarcopenia
  7. J Cell Physiol. 2020 Jun 15.
    Casuso RA, Al Fazazi S, Ruiz-Ojeda FJ, Plaza-Diaz J, Rueda-Robles A, Aragón-Vela J, Huertas JR.
      Training induces a number of healthy effects including a rise in skeletal muscle (SKM) glucose uptake. These adaptations are at least in part due to the reactive oxygen species produced within SKM, which is in agreement with the notion that antioxidant supplementation blunts some training-induced adaptations. Here, we tested whether hydroxytyrosol (HT), the main polyphenol of olive oil, would modify the molecular regulators of glucose uptake when HT is supplemented during exercise. Rats were included into sedentary and exercised (EXE) groups. EXE group was further divided into a group consuming a low HT dose (0.31 mg·kg·d; EXElow), a moderate HT dose (4.61 mg·kg·d; EXEmid), and a control group (EXE). EXE raised glucose transporter type 4 (GLUT4) protein content, Ras-related C3 botulinum toxin substrate 1 (Rac1) activity, and protein kinase b (AKT) phosphorylation in SKM. Furthermore, EXElow blunted GLUT4 protein content and AKT phosphorylation while EXEmid showed a downregulation of the GLUT4/AKT/Rac1 axis. Hence, a low-to-moderate dose of HT, when it is supplemented as an isolated compound, might alter the beneficial effect of training on basal AKT phosphorylation and Rac1 activity in rats.
    Keywords:  antioxidants; exercise; glucose; polyphenols; skeletal muscle
  8. Am J Physiol Endocrinol Metab. 2020 Jun 16.
    Miotto PM, Petrick HL, Holloway GP.
      Type 1 and type 2 diabetes are both tightly associated with impaired glucose control. While both pathologies stem from different mechanisms, a reduction in insulin action coincides with drastic metabolic dysfunction in skeletal muscle and metabolic inflexibility. However, the underlying explanation for this response remains poorly understood, particularly since it is difficult to distinguish the role of attenuated insulin action from the detrimental effects of reactive lipid accumulation which impair mitochondrial function and promote reactive oxygen species (ROS) emission. We therefore utilized streptozotocin to examine the effects of acute insulin deprivation, in the absence of a high lipid / nutrient excess environment, on the regulation of mitochondrial substrate sensitivity and ROS emission. The ablation of insulin resulted in reductions in absolute mitochondrial oxidative capacity, ADP-supported respiration, and reduced the ability for malonyl-CoA to inhibit carnitine palmitoyl-transferase I (CPT-I) and suppress fatty acid-supported respiration. These bioenergetic responses coincided with increased mitochondrial derived H2O2 emission and lipid transporter content, independent of major mitochondrial substrate transporter proteins and enzymes involved in fatty acid oxidation. Together, these data suggest that attenuated/ablated insulin signalling does not affect mitochondrial ADP sensitivity, while the increased reliance on fatty acid oxidation in situations where insulin action is reduced may occur as a result of altered regulation of mitochondrial fatty acid transport through CPT-I.
    Keywords:  ADP sensitivity; insulin; lipid metabolism; mitochondria; streptozotocin
  9. FEBS Lett. 2020 Jun 15.
    Park WJ, Park JW.
      The endoplasmic reticulum (ER) is an important intracellular compartment in eukaryotic cells and has diverse functions, including protein synthesis, protein folding, lipid metabolism, and calcium homeostasis. ER functions are disrupted by various intracellular and extracellular stimuli that cause ER stress, including the inhibition of glycosylation, disulphide bond reduction, ER calcium store depletion, impaired protein transport to the Golgi, excessive ER protein synthesis, impairment of ER-associated-protein-degradation, and mutated ER protein expression. Distinct ER stress signalling pathways, which are known as the unfolded protein response, are deployed to maintain ER homeostasis, and a failure to reverse ER stress triggers cell death. Sphingolipids are lipids that are structurally characterized by long-chain bases, including sphingosine or dihydrosphingosine (also known as sphinganine). Sphingolipids are bioactive molecules long known to regulate various cellular processes, including cell proliferation, migration, apoptosis, and cell-cell interaction. Recent studies have uncovered that specific sphingolipids are involved in ER stress. This review summarizes the roles of sphingolipids in ER stress and human diseases in the context of pathogenic events.
    Keywords:  Sphingolipid; acyl chain length; ceramide; disease; endoplasmic reticulum stress
  10. Trends Cell Biol. 2020 Jun 16. pii: S0962-8924(20)30101-X. [Epub ahead of print]
    Bhattarai KR, Chaudhary M, Kim HR, Chae HJ.
      Recent work provides evidence for the new terminology, 'endoplasmic reticulum (ER) stress response or sensing failure', in relation to metabolic disease. We seek to identify and amass possible conditions of ER stress response failure in various metabolic and age-related pathogenesis, including obesity and diabetes.
    Keywords:  ER proteostasis; ER stress; ER stress response failure; aging; metabolic diseases; sXBP1
  11. Proc Natl Acad Sci U S A. 2020 Jun 17. pii: 202002250. [Epub ahead of print]
    Chavez JD, Tang X, Campbell MD, Reyes G, Kramer PA, Stuppard R, Keller A, Zhang H, Rabinovitch PS, Marcinek DJ, Bruce JE.
      Mitochondrial dysfunction underlies the etiology of a broad spectrum of diseases including heart disease, cancer, neurodegenerative diseases, and the general aging process. Therapeutics that restore healthy mitochondrial function hold promise for treatment of these conditions. The synthetic tetrapeptide, elamipretide (SS-31), improves mitochondrial function, but mechanistic details of its pharmacological effects are unknown. Reportedly, SS-31 primarily interacts with the phospholipid cardiolipin in the inner mitochondrial membrane. Here we utilize chemical cross-linking with mass spectrometry to identify protein interactors of SS-31 in mitochondria. The SS-31-interacting proteins, all known cardiolipin binders, fall into two groups, those involved in ATP production through the oxidative phosphorylation pathway and those involved in 2-oxoglutarate metabolic processes. Residues cross-linked with SS-31 reveal binding regions that in many cases, are proximal to cardiolipin-protein interacting regions. These results offer a glimpse of the protein interaction landscape of SS-31 and provide mechanistic insight relevant to SS-31 mitochondrial therapy.
    Keywords:  aging; cross-linking; interactome; mitochondria