bims-misrem Biomed News
on Mitochondria and sarcoplasmic reticulum in muscle mass
Issue of 2020‒04‒12
fourteen papers selected by
Rafael Antonio Casuso Pérez
University of Granada


  1. J Gerontol A Biol Sci Med Sci. 2020 Apr 07. pii: glaa082. [Epub ahead of print]
    Berg OK, Kwon OS, Hureau TJ, Clifton HL, Thurston TS, Le Fur Y, Jeong EK, Trinity JD, Richardson RS, Wang E, Layec G.
      Maximal Strength Training (MST) results in robust improvements in skeletal muscle force production, efficiency, and mass. However, the effects of MST on muscle mitochondria is still unknown. Accordingly, the purpose of this study was to examine, from the molecular level to whole-muscle, mitochondrial adaptations induced by 8 weeks of knee-extension MST in the quadriceps of 10 older adults using immunoblotting, spectrophotometry, high-resolution respirometry in permeabilized muscle fibers, in vivo31P magnetic resonance spectroscopy (31P-MRS) and gas exchange. As anticipated, MST resulted in an increased isometric knee-extensor force from 133±36 to 147±49 Nm (P<0.05) and quadriceps muscle volume from 1410±103 to 1555±455 cm3 (P<0.05). Mitochondrial complex (I-V) protein abundance and citrate synthase activity were not significantly altered by MST. Assessed ex vivo, maximal ADP-stimulated respiration (state 3CI+CII, PRE: 23±6 and POST: 14±5 ρM·mg-1·s-1, P<0.05), was decreased by MST, predominantly, as a result of a decline in complex I linked respiration (P<0.05). Additionally, state 3 free-fatty acid linked respiration was decreased following MST (PRE: 19±5 and POST: 14±3 ρM·mg-1·s-1, P<0.05). Assessed in vivo, MST slowed the PCr recovery time constant (PRE: 49±13 and POST: 57±16 s, P<0.05) and lowered, by ~20% (P=0.055), the quadriceps peak rate of oxidative ATP synthesis, but did not significantly alter the oxidation of lipid. Although these, likely qualitative, mitochondrial adaptations are potentially negative in terms of skeletal muscle energetic capacity, they need to be considered in light of the many improvements in muscle function that MST affords older adults.
    Keywords:  31P-MRS; mitochondrial function; strength training
    DOI:  https://doi.org/10.1093/gerona/glaa082
  2. Redox Biol. 2020 Apr 01. pii: S2213-2317(20)30131-2. [Epub ahead of print] 101529
    Hernández-Camacho JD, Vicente-García C, Parsons DS, Navas-Enamorado I.
      Zinc is an essential element for all forms of life, and one in every ten human proteins is a zinc protein. Zinc has catalytic, structural and signalling functions and its correct homeostasis affects many cellular processes. Zinc deficiency leads to detrimental consequences, especially in tissues with high demand such as skeletal muscle. Zinc cellular homeostasis is tightly regulated by different transport and buffer protein systems. Specifically, in skeletal muscle, zinc has been found to affect myogenesis and muscle regeneration due to its effects on muscle cell activation, proliferation and differentiation. In relation to skeletal muscle, exercise has been shown to modulate zinc serum and urinary levels and could directly affect cellular zinc transport. The oxidative stress induced by exercise may provide the basis for the mild zinc deficiency observed in athletes and could have severe consequences on health and sport performance. Proteostasis is induced during exercise and zinc plays an essential role in several of the associated pathways.
    Keywords:  Exercise; Physical performance; Skeletal muscle; Zinc homeostasis; Zinc regulation
    DOI:  https://doi.org/10.1016/j.redox.2020.101529
  3. Sci Rep. 2020 Apr 08. 10(1): 6095
    Zhao H, Lewellen BM, Wilson RJ, Cui D, Drake JC, Zhang M, Yan Z.
      The common clinical symptoms of Friedreich's ataxia (FRDA) include ataxia, muscle weakness, type 2 diabetes and heart failure, which are caused by impaired mitochondrial function due to the loss of frataxin (FXN) expression. Endurance exercise is the most powerful intervention for promoting mitochondrial function; however, its impact on FRDA has not been studied. Here we found that mice with genetic knockout and knock-in of the Fxn gene (KIKO mice) developed exercise intolerance, glucose intolerance and moderate cardiac dysfunction at 6 months of age. These abnormalities were associated with impaired mitochondrial respiratory function concurrent with reduced iron regulatory protein 1 (Irp1) expression as well as increased oxidative stress, which were not due to loss of mitochondrial content and antioxidant enzyme expression. Importantly, long-term (4 months) voluntary running in KIKO mice starting at a young age (2 months) completely prevented the functional abnormalities along with restored Irp1 expression, improved mitochondrial function and reduced oxidative stress in skeletal muscle without restoring Fxn expression. We conclude that endurance exercise training prevents symptomatic onset of FRDA in mice associated with improved mitochondrial function and reduced oxidative stress. These preclinical findings may pave the way for clinical studies of the impact of endurance exercise in FRDA patients.
    DOI:  https://doi.org/10.1038/s41598-020-62952-6
  4. Front Cell Dev Biol. 2020 ;8 200
    Chen G, Kroemer G, Kepp O.
      Mitochondrial dysfunction constitutes one of the hallmarks of aging and is characterized by irregular mitochondrial morphology, insufficient ATP production, accumulation of mitochondrial DNA (mtDNA) mutations, increased production of mitochondrial reactive oxygen species (ROS) and the consequent oxidative damage to nucleic acids, proteins and lipids. Mitophagy, a mitochondrial quality control mechanism enabling the degradation of damaged and superfluous mitochondria, prevents such detrimental effects and reinstates cellular homeostasis in response to stress. To date, there is increasing evidence that mitophagy is significantly impaired in several human pathologies including aging and age-related diseases such as neurodegenerative disorders, cardiovascular pathologies and cancer. Therapeutic interventions aiming at the induction of mitophagy may have the potency to ameliorate these dysfunctions. In this review, we summarize recent findings on mechanisms controlling mitophagy and its role in aging and the development of human pathologies.
    Keywords:  ROS; aging; caloric restriction; mitochondria; mitophagy
    DOI:  https://doi.org/10.3389/fcell.2020.00200
  5. J Cell Biol. 2020 Jun 01. pii: e201907067. [Epub ahead of print]219(6):
    Liu YJ, McIntyre RL, Janssens GE, Williams EG, Lan J, van Weeghel M, Schomakers B, van der Veen H, van der Wel NN, Yao P, Mair WB, Aebersold R, MacInnes AW, Houtkooper RH.
      Mitochondrial form and function are closely interlinked in homeostasis and aging. Inhibiting mitochondrial translation is known to increase lifespan in C. elegans, and is accompanied by a fragmented mitochondrial network. However, whether this link between mitochondrial translation and morphology is causal in longevity remains uncharacterized. Here, we show in C. elegans that disrupting mitochondrial network homeostasis by blocking fission or fusion synergizes with reduced mitochondrial translation to prolong lifespan and stimulate stress response such as the mitochondrial unfolded protein response, UPRMT. Conversely, immobilizing the mitochondrial network through a simultaneous disruption of fission and fusion abrogates the lifespan increase induced by mitochondrial translation inhibition. Furthermore, we find that the synergistic effect of inhibiting both mitochondrial translation and dynamics on lifespan, despite stimulating UPRMT, does not require it. Instead, this lifespan-extending synergy is exclusively dependent on the lysosome biogenesis and autophagy transcription factor HLH-30/TFEB. Altogether, our study reveals the mechanistic crosstalk between mitochondrial translation, mitochondrial dynamics, and lysosomal signaling in regulating longevity.
    DOI:  https://doi.org/10.1083/jcb.201907067
  6. Mol Metab. 2020 Apr 06. pii: S2212-8778(20)30063-6. [Epub ahead of print] 100989
    Held NM, Wefers J, van Weeghel M, Daemen S, Hansen J, Vaz FM, van Moorsel D, Hesselink MKC, Houtkooper RH, Schrauwen P.
      OBJECTIVE: Human energy metabolism is under the regulation of the molecular circadian clock; we recently reported that mitochondrial respiration displays a day-night rhythm under study conditions that are similar to real life. Mitochondria are interconnected with lipid droplets, which are of importance in fuel utilization and play a role in muscle insulin sensitivity. Here, we investigated if skeletal muscle lipid content and composition also displays day-night rhythmicity in healthy, lean volunteers.METHODS: Skeletal muscle biopsies were obtained from 12 healthy lean male volunteers every 5h over a 24h period. Volunteers were provided with standardized meals, and biopsies were taken 4.5h after each last meal. Lipid droplet size and number were investigated by confocal microscopy. Additionally, the muscle lipidome was assessed using UPLC/HRMS-based semi-targeted lipidomics.
    RESULTS: Confocal microscopy revealed diurnal differences in intramyocellular lipid content (p < 0.05) and lipid droplet size in oxidative type 1 muscle fibers (p < 0.01). Lipidomics analysis revealed that 13% of all detected lipids displayed significant day-night rhythmicity. The most rhythmic lipid species were glycerophospholipids and diacylglycerols (DAG), with the latter being the largest fraction (>50% of all rhythmic species). DAG levels showed a day-night pattern with a trough at 1PM and a peak at 4AM.
    CONCLUSIONS: Using two distinct methods, our findings show that myocellular lipid content and whole muscle lipid composition varies across the day-night cycle under normal living conditions. In particular, day-night rhythmicity was present in over half of DAG lipid species. Future studies are needed to investigate whether rhythmicity in DAG is functionally related to insulin sensitivity and how this might be altered in prediabetes.
    Keywords:  Circadian clock; Lipidomics; human skeletal muscle; lipid metabolism
    DOI:  https://doi.org/10.1016/j.molmet.2020.100989
  7. J Appl Physiol (1985). 2020 Apr 09.
    Woodhead JST, D'Souza RF, Hedges CP, Wan J, Berridge MV, Cameron-Smith D, Cohen P, Hickey AJR, Mitchell CJ, Merry TL.
      Humanin, a small regulatory peptide encoded within the 16S ribosomal RNA gene (MT-RNR2) of the mitochondrial genome, has cellular cyto- and metabolo-protective properties similar to that of aerobic exercise training. Here we investigated whether acute high-intensity interval exercise or short-term high-intensity interval training (HIIT) impacted skeletal muscle and plasma humanin levels. Vastus lateralis muscle biopsies and plasma samples were collected from young healthy untrained men (n=10, 24.5±3.7 y) before, immediately following, and 4 h following the completion of 10 x 60 s cycle ergometer bouts at VO2peak power output (untrained). Resting and post-exercise sampling was also performed after six HIIT sessions (trained) completed over 2 weeks. Humanin protein abundance in muscle and plasma were increased following an acute high-intensity exercise bout. HIIT trended (p=0.063) to lower absolute humanin plasma levels, without effecting the response in muscle or plasma to acute exercise. A similar response in the plasma was observed for the small humanin-like peptide 6 (SHLP6), but not SHLP2, indicating selective regulation of peptides encoded by MT-RNR2 gene. There was a weak positive correlation between muscle and plasma humanin levels, and contraction of isolated mouse EDL muscle increased humanin levels approximately 4-fold. The increase in muscle humanin levels with acute exercise was not associated with MT-RNR2 mRNA or humanin mRNA levels (which decreased following acute exercise). Overall, these results suggest that humanin is an exercise sensitive mitochondrial peptide and acute exercise-induced humanin responses in muscle are non-transcriptionally regulated and may partially contribute to the observed increase in plasma concentrations.
    Keywords:  exercise; mitochondrial derived peptides; mitokine; muscle; small humanin-like peptides
    DOI:  https://doi.org/10.1152/japplphysiol.00032.2020
  8. J Cell Sci. 2020 Apr 07. pii: jcs.237917. [Epub ahead of print]
    Martinez-Guzman O, Willoughby MM, Saini A, Dietz JV, Bohovych I, Medlock AE, Khalimonchuk O, Reddi AR.
      Heme is a cofactor and signaling molecule that is essential for much of aerobic life. All heme-dependent processes in eukaryotes require that heme is trafficked from its site of synthesis in the mitochondria to hemoproteins located throughout the cell. However, the mechanisms governing the mobilization of heme out of the mitochondria, and the spatio-temporal dynamics of these processes, are poorly understood. Herein, using genetically encoded fluorescent heme sensors, we developed a live cell assay to monitor heme distribution dynamics between the mitochondrial inner-membrane, where heme is synthesized, and the mitochondrial matrix, cytosol, and nucleus. Surprisingly, heme trafficking to the nucleus is ∼25% faster than to the cytosol or mitochondrial matrix, which are nearly identical, potentially supporting a role for heme as a mitochondrial-nuclear retrograde signal. Moreover, we discovered that the heme synthetic enzyme, 5-aminolevulinic acid synthase (ALAS), and GTPases in control of the mitochondrial dynamics machinery, Mgm1 and Dnm1, and ER contact sites, Gem1, regulate the flow of heme between the mitochondria and nucleus. Overall, our results indicate that there are parallel pathways for the distribution of bioavailable heme.
    Keywords:  Heme; Heme transport; Mitochondrial dynamics; Yeast
    DOI:  https://doi.org/10.1242/jcs.237917
  9. J Microsc. 2020 Apr 11.
    Faitg J, Davey T, Turnbull DM, White K, Vincent AE.
      Mitochondrial shape and function are known to be linked, therefore there is a need to combine three-dimensional EM structural analysis with functional analysis. Cytochrome c oxidase labelling is one approach to examine mitochondrial function at the EM level. However, previous efforts to apply this method have had several issues including inconsistent results, disruption to mitochondrial ultrastructure, and a lack of optimisation for volume EM methods. We have used short fixation and microwave processing to address these issues. We show that our method gives consistent cytochrome c oxidase labelling and improves labelling penetration across tissue volume. We also quantify mitochondrial morphology metrics, including in volume EM, to show that ultrastructure is unaltered by the processing. This work represents a technical advance that allows the correlation of mitochondrial function and morphology with greater resolution and volume than has previously been feasible. This article is protected by copyright. All rights reserved.
    Keywords:  COX; EM; SBFSEM; TEM; cytochemistry; mitochondria
    DOI:  https://doi.org/10.1111/jmi.12891
  10. Trends Endocrinol Metab. 2020 Apr 04. pii: S1043-2760(20)30060-6. [Epub ahead of print]
    Rocha M, Apostolova N, Diaz-Rua R, Muntane J, Victor VM.
      Type 2 diabetes (T2D) is one of the main current threats to human health. Both T2D and its numerous clinical complications are related to mitochondrial dysfunction and oxidative stress. Over the past decade, great progress has been made in extending our knowledge about the signaling events regulated by mitochondria. However, the links among mitochondrial impairment, oxidative stress, autophagy, endoplasmic reticulum (ER) stress, and activation of the inflammasome still need to be clarified. In light of this deficit, we aim to provide a review of the existing literature concerning the complicated crosstalk between mitochondrial impairment, autophagy, ER stress, and the inflammasome in the molecular pathogenesis of T2D.
    Keywords:  autophagy; endoplasmic reticulum stress; inflammasome; mitochondria; oxidative stress; type 2 diabetes
    DOI:  https://doi.org/10.1016/j.tem.2020.03.004
  11. Nutr Metab (Lond). 2020 ;17 26
    Yin L, Lu L, Lin X, Wang X.
      Background: Androgen receptor (AR) has been reported to play vital roles in exercise-induced increase of muscle mass in rats, but needs to be further verified and the mechanism behind remains unclear. As AR target genes, insulin growth factor-1 (IGF-1) and IGF-1 receptor (IGF-1R) promote muscle hypertrophy through activating PI3K/Akt- mammalian target of rapamycin (mTOR) pathway, a classic pathway of muscle hypertrophy. So the main purpose of this study was using AR antagonist flutamide to demonstrate AR's effect on training-induced muscle hypertrophy and its possible mechanism: IGF-1/IGF-1R- PI3K/Akt- mTOR pathway?Methods: Forty-eight Sprague Dawley male rats aged 7 weeks were randomly divided into six groups: control (C), flutamide (F), resistance training (R), resistance training plus flutamide (R + F), endurance training (E), and endurance training plus flutamide (E + F) groups. Flutamide was used to block AR in rats. Rats in R and R + F groups fulfilled 3 weeks of ladder climbing with progressively increased load, while E and E + F rats completed 3-week moderate intensity aerobic exercise on a treadmill. The relative muscle mass (muscle mass/body weight) of rats was detected. Serum levels of testosterone and IGF-1 of rats were determined by ELISA, and mRNA levels of IGF-1R and mTOR in muscles by real-time PCR. Protein levels of AR, IGF-1, IGF-1R, mTOR, PI3K, Akt, p-PI3K and p-Akt in muscles were detected by Western blot.
    Results: (1) The training-induced rise in the relative muscle mass and the expression levels of AR were only found in the gastrocnemius of R rats and in the soleus of E rats (selective muscle hypertrophy), which were blocked by flutamide. (2) Serum testosterone in the R and E rat were increased, and flutamide exerted no effect. (3) The levels of IGF-1, IGF-1R and mTOR as well as the activities of PI3K and Akt were enhanced selectively (in the gastrocnemius of R rats and in the soleus of E rats), which were reduced by flutamide. Conclusions: AR exerted an essential role in both resistance training and endurance training-induced muscle hypertrophy, which was mediated at least partly through IGF-1/IGF-1R- PI3K/Akt- mTOR pathway.
    Keywords:  Androgen receptor; IGF-1; IGF-1R; Muscle hypertrophy; PI3K/Akt/mTOR; Training
    DOI:  https://doi.org/10.1186/s12986-020-00446-y
  12. Autophagy. 2020 Apr 08.
    Call JA, Nichenko AS.
      Macroautophagy/autophagy induction, i.e., the formation of autophagosomes, is robust following many forms of muscle injury. Autophagy inhibition studies strongly indicate that autophagy is necessary for successful muscle fiber recovery. Now, there are accumulating pieces of evidence indicating that autophagosome clearance, i.e., autophagy flux, does not increase to match the burden of accumulating damaged proteins and organelles after muscle fiber damage, creating a bottleneck effect. Some potential consequences of the bottleneck effect are reduced regenerative capacity marked by the inadequate activation of muscle stem cells (i.e., satellite cells) and a lesser commitment towards differentiation due to a deficiency in energetic substrates and/or molecular signaling pathways. These findings highlight an emerging area of investigation for both autophagy and muscle regeneration fields. The identification of the molecular mechanisms governing autophagy and autophagy flux may serve as targets for future therapies to enhance the recovery of its function in healthy and diseased muscle.
    Keywords:  ULK1; mitochondria; mitophagy; muscle regeneration; muscle strength; satellite cell; two-photon microscopy
    DOI:  https://doi.org/10.1080/15548627.2020.1753000
  13. Protein Pept Lett. 2020 Apr 07.
    Wang BC, Zhang ST, Chen G.
      The unfolded protein response (UPR) is a protective mechanism against endoplasmic reticulum (ER) stress that induces a series of signal transduction pathways to eliminate misfolded proteins. The UPR mechanism is highly conserved in fungi, higher organisms, plants and mammals. The UPR pathway is activated to stabilize ER functions when there are too many unfolded proteins or misfolded proteins in the ER. However, stress continues when ER proteins are stimulated by toxic substances that affect the balance of the UPR pathway, which causes changes in the structure and function of the ER and other organelles. These ultimately disrupt homeostasis in the body and cause pathological reactions that can be fatal. The UPR mechanism has clear effects on stabilizing the protein-folding environment. Dysfunction or disruption of the UPR mechanism is associated with numerous disorders, including neurodegenerative diseases, loss of control of protein secretion, cerebral ischemia and epilepsy, neuropsychiatric diseases, eye diseases, skin diseases, metabolic and inflammatory diseases, atherosclerosis, and heart disease. Thus, characterization of UPR function and its dysfunction has significant importance and has broad application prospects, which make research into the UPR a research hotspot.
    Keywords:  Endoplasmic reticulum stress; gene expression regulation; homeostasis.; misfolded proteins UPR pathway; unfolded protein response
    DOI:  https://doi.org/10.2174/0929866527666200407113549