bims-misrem Biomed News
on Mitochondria and sarcoplasmic reticulum in muscle mass
Issue of 2020‒05‒31
nineteen papers selected by
Rafael Antonio Casuso Pérez
University of Granada


  1. J Cell Physiol. 2020 May 26.
    Houzelle A, Dahlmans D, Nascimento EBM, Schaart G, Jörgensen JA, Moonen-Kornips E, Kersten S, Wang X, Hoeks J.
      Using an unbiased high-throughput microRNA (miRNA)-silencing screen combined with functional readouts for mitochondrial oxidative capacity in C2C12 myocytes, we previously identified 19 miRNAs as putative regulators of skeletal muscle mitochondrial metabolism. In the current study, we highlight miRNA-204-5p, identified from this screen, and further studied its role in the regulation of skeletal muscle mitochondrial function. Following silencing of miRNA-204-5p in C2C12 myotubes, gene and protein expression were assessed using quantitative polymerase chain reaction, microarray analysis, and western blot analysis, while morphological changes were studied by confocal microscopy. In addition, miRNA-204-5p expression was quantified in human skeletal muscle biopsies and associated with in vivo mitochondrial oxidative capacity. Transcript levels of PGC-1α (3.71-fold; p  <  .01), predicted as an miR-204-5p target, as well as mitochondrial DNA copy number (p <  .05) and citrate synthase activity (p  =  .06) were increased upon miRNA-204-5p silencing in C2C12 myotubes. Silencing of miRNA-204-5p further resulted in morphological changes, induced gene expression of autophagy marker light chain 3 protein b (LC3B; q  =  .05), and reduced expression of the mitophagy marker FUNDC1 (q  =  .01). Confocal imaging revealed colocalization between the autophagosome marker LC3B and the mitochondrial marker OxPhos upon miRNA-204-5p silencing. Finally, miRNA-204-5p was differentially expressed in human subjects displaying large variation in oxidative capacity and its expression levels associated with in vivo measures of skeletal muscle mitochondrial function. In summary, silencing of miRNA-204-5p in C2C12 myotubes stimulated mitochondrial biogenesis, impacted on cellular morphology, and altered expression of markers related to autophagy and mitophagy. The association between miRNA-204-5p and in vivo mitochondrial function in human skeletal muscle further identifies miRNA-204-5p as an interesting modulator of skeletal muscle mitochondrial metabolism.
    Keywords:  C2C12; microRNA; mitochondria; mitophagy; skeletal muscle
    DOI:  https://doi.org/10.1002/jcp.29797
  2. Exp Physiol. 2020 May 29.
    Mir BA, Mason SA, May AK, Russell AP, Foletta VC.
      NEW FINDINGS: What is the central question of this study? Do elevated levels of the stress-response NDRG2 protein protect against fasting and chronic disease in mouse skeletal muscle? What is the main finding and its importance? NDRG2 levels increased in response to fasting and motor neurone disease effects in the tibialis anterior muscle. No alleviation of the stress-related and proteasomal pathways, mitochondrial dysfunction or muscle mass loss was observed even with further exogenous NDRG2 added indicating that the increased NDRG2 in skeletal muscle is simply a normal adaptive response.ABSTRACT: Skeletal muscle mass loss and dysfunction can arise from stress leading to enhanced protein degradation and metabolic impairment. The expression of N-myc downstream-regulated gene 2 (NDRG2) is induced in response to different stressors and is protective against the effects of stress in some tissues and cell types. Here, we investigated endogenous NDRG2 response to fasting and chronic disease stress in mice, and whether exogenous NDRG2 overexpression through adeno-associated viral (AAV) treatment ameliorated skeletal muscle's response to these conditions. Endogenous levels of NDRG2 increased in the tibialis anterior muscle in response to 24 h fasting and with the development of the motor neurone disease, amyotrophic lateral sclerosis, in SOD1G93A transgenic mice. Despite AAV-induced overexpression and increased expression with fasting, NDRG2 was unable to protect against the activation of proteasomal and stress pathways in response to fasting. Furthermore, NDRG2 was unable to reduce muscle mass loss, mitochondrial dysfunction, and elevated oxidative and endoplasmic reticulum stress levels in SOD1G93A mice. Conversely, elevated NDRG2 levels did not exacerbate these stress responses. Overall, increasing NDRG2 levels may not be a useful therapeutic strategy to alleviate stress-related disease pathologies in skeletal muscle. This article is protected by copyright. All rights reserved.
    Keywords:  N-myc downstream-regulated gene 2 (NDRG2); SOD1G93A mice; fasting; skeletal muscle; stress response
    DOI:  https://doi.org/10.1113/EP088620
  3. Exp Gerontol. 2020 May 22. pii: S0531-5565(20)30320-X. [Epub ahead of print]137 110972
    Custodero C, Saini SK, Shin MJ, Jeon YK, Christou DD, McDermott MM, Leeuwenburgh C, Anton SD, Mankowski RT.
      Maintaining physical mobility is important for preventing age-related comorbidities in older adults. Endurance and resistance training prevent mobility loss in aging, but exercise alone does not always achieve the expected improvements in physical and cardiopulmonary function. Recent preclinical evidence suggests that a reason for the variability in exercise training responses may be the age-related dysregulation of the nicotinamide adenine dinucleotide (NAD+) metabolome. NAD+ is an essential enzymatic cofactor in energetic and signaling pathways. Endogenous NAD+ pool is lower in several chronic and degenerative diseases (e.g., cardiovascular diseases, Alzheimer's and Parkinson's diseases, muscular dystrophies), and also in aging. Exercise requires a higher energy expenditure than a resting state, thus a state of NAD+ insufficiency with reduced energy metabolism, could result in an inadequate exercise response. Recently, the NAD+ precursor nicotinamide riboside (NR), a vitamin B3 derivate, showed an ability to improve NAD+ metabolome homeostasis, restoring energy metabolism and cellular function in various organs in animals. NR has also been tested in older humans and is considered safe, but the effects of NR supplementation alone on physical performance are unclear. The purpose of this review is to examine the preclinical and clinical evidence on the effect of NR supplementation strategies alone and in combination with physical activity on mobility and skeletal muscle and cardiovascular function.
    Keywords:  Cardiovascular function; Exercise training; NAD+ metabolome; Nicotinamide riboside; Older adults; Skeletal muscle
    DOI:  https://doi.org/10.1016/j.exger.2020.110972
  4. Biochem Biophys Res Commun. 2020 Jun 18. pii: S0006-291X(20)30788-9. [Epub ahead of print]527(1): 146-152
    Yokokawa T, Mori R, Suga T, Isaka T, Hayashi T, Fujita S.
      The mitochondrial translation process, in which mitochondrial DNA (mtDNA)-encoded genes are translated into their corresponding proteins, is crucial for mitochondrial function, biogenesis, and integrity. This process is divided into four phases-initiation, elongation, termination, and mitoribosome recycling-which are regulated by specific translation factors, including mitochondrial initiation factor 2 and 3 (mtIF2 and mtIF3), mitochondrial elongation factor Tu, Ts, and G1 (mtEFTu, mtEFTs, and mtEFG1), mitochondrial translational release factor 1-like (mtRF1L), and mitochondrial recycling factor 1 and 2 (mtRRF1 and mtRRF2). Muscle denervation downregulates mitochondrial biomass and induces skeletal muscle atrophy. However, it is unknown whether denervation affects the expression of mitochondrial translation factors in skeletal muscle. In this study, we hypothesized that denervation decreases the expression of mitochondrial translation factors. Therefore, we investigated the effect of muscle denervation on mitochondrial protein and mitochondrial translation factor expression in soleus muscle after surgery. Denervation induced muscle atrophy and activated the ubiquitin-proteasome pathway in soleus muscle. Additionally, muscle denervation decreased the expression of mitochondrial translation factors as well as nuclear DNA and mtDNA-encoded mitochondrial proteins in soleus muscle. Further, a correlation was found between the expression of mitochondrial translation factors and mtDNA-encoded proteins three and seven days after denervation. Taken together, these results demonstrated that the denervation-induced decrease in mitochondrial biogenesis corresponded with changes in mitochondrial translation factors in murine skeletal muscle, providing novel molecular-level insight into the effects of muscle denervation on the mitochondrial translation process.
    Keywords:  Denervation; Mitochondrial biogenesis; Mitochondrial translation factor; Skeletal muscle
    DOI:  https://doi.org/10.1016/j.bbrc.2020.04.062
  5. Trends Cancer. 2020 May 22. pii: S2405-8033(20)30139-4. [Epub ahead of print]
    O'Malley J, Kumar R, Inigo J, Yadava N, Chandra D.
      Cancer cells survive and adapt to many types of stress including hypoxia, nutrient deprivation, metabolic, and oxidative stress. These stresses are sensed by diverse cellular signaling processes, leading to either degradation of mitochondria or alleviation of mitochondrial stress. This review discusses signaling during sensing and mitigation of stress involving mitochondrial communication with the endoplasmic reticulum, and how retrograde signaling upregulates the mitochondrial stress response to maintain mitochondrial integrity. The importance of the mitochondrial unfolded protein response, an emerging pathway that alleviates cellular stress, will be elaborated with respect to cancer. Detailed understanding of cellular pathways will establish mitochondrial stress response as a key mechanism for cancer cell survival leading to cancer progression and resistance, and provide a potential therapeutic target in cancer.
    Keywords:  cancer cell survival; cancer progression; heat shock protein 60; mitochondrial stress response; mitochondrial unfolded protein response; therapeutic resistance
    DOI:  https://doi.org/10.1016/j.trecan.2020.04.009
  6. Nat Rev Mol Cell Biol. 2020 May 26.
    Hetz C, Zhang K, Kaufman RJ.
      Cellular stress induced by the abnormal accumulation of unfolded or misfolded proteins at the endoplasmic reticulum (ER) is emerging as a possible driver of human diseases, including cancer, diabetes, obesity and neurodegeneration. ER proteostasis surveillance is mediated by the unfolded protein response (UPR), a signal transduction pathway that senses the fidelity of protein folding in the ER lumen. The UPR transmits information about protein folding status to the nucleus and cytosol to adjust the protein folding capacity of the cell or, in the event of chronic damage, induce apoptotic cell death. Recent advances in the understanding of the regulation of UPR signalling and its implications in the pathophysiology of disease might open new therapeutic avenues.
    DOI:  https://doi.org/10.1038/s41580-020-0250-z
  7. Biogerontology. 2020 May 23.
    Thoma A, Akter-Miah T, Reade RL, Lightfoot AP.
      The loss of muscle mass and function with age, termed sarcopenia, is an inevitable process, which has a significant impact on quality of life. During ageing we observe a progressive loss of total muscle fibres and a reduction in cross-sectional area of the remaining fibres, resulting in a significant reduction in force output. The mechanisms which underpin sarcopenia are complex and poorly understood, ranging from inflammation, dysregulation of protein metabolism and denervation. However, there is significant evidence to demonstrate that modified ROS generation, redox dis-homeostasis and mitochondrial dysfunction may have an important role to play. Based on this, significant interest and research has interrogated potential ROS-targeted therapies, ranging from nutritional-based interventions such as vitamin E/C, polyphenols (resveratrol) and targeted pharmacological compounds, using molecules such as SS-31 and MitoQ. In this review we evaluate these approaches to target aberrant age-related ROS generation and the impact on muscle mass and function.
    Keywords:  Ageing; Mitochondria; Oxidative stress; Reactive oxygen species; Sarcopenia
    DOI:  https://doi.org/10.1007/s10522-020-09883-x
  8. Eur J Appl Physiol. 2020 May 26.
    Pham T, MacRae CL, Broome SC, D'souza RF, Narang R, Wang HW, Mori TA, Hickey AJR, Mitchell CJ, Merry TL.
      PURPOSE: Excess production of reactive oxygen species (ROS) from the mitochondria can promote mitochondrial dysfunction and has been implicated in the development of a range of chronic diseases. As such there is interest in whether mitochondrial-targeted antioxidant supplementation can attenuate mitochondrial-associated oxidative stress. We investigated the effect of MitoQ and CoQ10 supplementation on oxidative stress and skeletal muscle mitochondrial ROS levels and function in healthy middle-aged men.METHODS: Skeletal muscle and blood samples were collected from twenty men (50 ± 1 y) before and following six weeks of daily supplementation with MitoQ (20 mg) or CoQ10 (200 mg). High-resolution respirometry was used to determine mitochondrial respiration and H2O2 levels, markers of mitochondrial mass and antioxidant defences were measured in muscle samples and oxidative stress markers in urine and blood samples.
    RESULTS: Both MitoQ and CoQ10 supplementation suppressed mitochondrial net H2O2 levels during leak respiration, while MitoQ also elevated muscle catalase expression. However, neither supplement altered urine F2-isoprostanes nor plasma TBARS levels. Neither MitoQ nor CoQ10 supplementation had a significant impact on mitochondrial respiration or mitochondrial density markers (citrate synthase, mtDNA/nDNA, PPARGC1A, OXPHOS expression).
    CONCLUSION: Our results suggest that neither MitoQ and CoQ10 supplements impact mitochondrial function, but both can mildly suppress mitochondrial ROS levels in healthy middle-aged men, with some indication that MitoQ may be more effective than CoQ10.
    Keywords:  Antioxidant; Mitochondria; Muscle; Oxidative stress; ROS
    DOI:  https://doi.org/10.1007/s00421-020-04396-4
  9. Int J Sports Med. 2020 May 26.
    Nikolaidis MG, Margaritelis NV, Matsakas A.
      Biology is rich in claims that reactive oxygen and nitrogen species are involved in every biological process and disease. However, many quantitative aspects of redox biology remain elusive. The important quantitative parameters you need to address the feasibility of redox reactions in vivo are: rate of formation and consumption of a reactive oxygen and nitrogen species, half-life, diffusibility and membrane permeability. In the first part, we explain the basic chemical kinetics concepts and algebraic equations required to perform "street fighting" quantitative analysis. In the second part, we provide key numbers to help thinking about sizes, concentrations, rates and other important quantities that describe the major oxidants (superoxide, hydrogen peroxide, nitric oxide) and antioxidants (vitamin C, vitamin E, glutathione). In the third part, we present the quantitative effect of exercise on superoxide, hydrogen peroxide and nitric oxide concentration in mitochondria and whole muscle and calculate how much hydrogen peroxide concentration needs to increase to transduce signalling. By taking into consideration the quantitative aspects of redox biology we can: i) refine the broad understanding of this research area, ii) design better future studies and facilitate comparisons among studies, and iii) define more efficiently the "borders" between cellular signaling and stress.
    DOI:  https://doi.org/10.1055/a-1157-9043
  10. J Bioenerg Biomembr. 2020 May 27.
    Serna JDC, Caldeira da Silva CC, Kowaltowski AJ.
      Caloric restriction (CR) is widely known to increase life span and resistance to different types of injuries in several organisms. We have previously shown that mitochondria from livers or brains of CR animals exhibit higher calcium uptake rates and lower sensitivity to calcium-induced mitochondrial permeability transition (mPT), an event related to the resilient phenotype exhibited by these organs. Given the importance of calcium in metabolic control and cell homeostasis, we aimed here to uncover possible changes in mitochondrial calcium handling, redox balance and bioenergetics in cardiac and skeletal muscle mitochondria in response to six months of CR. Unexpectedly, we found that CR does not alter the susceptibility to mPT in muscle (cardiac or skeletal), nor calcium uptake rates. Despite the lack in changes in calcium transport properties, CR consistently decreased respiration in the presence of ATP synthesis in heart and soleus muscle. In heart, such changes were accompanied by a decrease in respiration in the absence of ATP synthesis, lower maximal respiratory rates and a reduced rate of hydrogen peroxide release. Hydrogen peroxide release was unaltered by CR in skeletal muscle. No changes were observed in inner membrane potentials and respiratory control ratios. Together, these results highlight the tissue-specific bioenergetic and ion transport effects induced by CR, demonstrating that resilience against calcium-induced mPT is not present in all tissues.
    Keywords:  Bioenergetics; Caloric Restriction; Heart; Mitochondrial Permeability Transition; Reactive Oxygen Species; Soleus Muscle
    DOI:  https://doi.org/10.1007/s10863-020-09838-4
  11. Mol Neurobiol. 2020 May 25.
    Wang WX, Prajapati P, Nelson PT, Springer JE.
      The mitochondria-associated endoplasmic reticulum (ER) membranes (MAMs) are specific ER domains that contact the mitochondria and function to facilitate communication between ER and mitochondria. Disruption of contact between the mitochondria and ER is associated with a variety of pathophysiological conditions including neurodegenerative diseases. Considering the many cellular functions of MAMs, we hypothesized that MAMs play an important role in regulating microRNA (miRNA) activity linked to its unique location between mitochondria and ER. Here we present new findings from human and rat brains indicating that the MAMs are subcellular sites enriched for specific miRNAs. We employed subcellular fractionation and TaqMan® RT-qPCR miRNA analysis to quantify miRNA levels in subcellular fractions isolated from male rat brains and six human brain samples. We found that MAMs contain a substantial number of miRNAs and the profile differs significantly from that of cytosolic, mitochondria, or ER. Interestingly, MAMs are particularly enriched in inflammatory-responsive miRNAs, including miR-146a, miR-142-3p, and miR-142-5p in both human and rat brains; miR-223 MAM enrichment was observed only in human brain samples. Further, mitochondrial uncoupling or traumatic brain injury in male rats resulted in the alteration of inflammatory miRNA enrichment in the isolated subcellular fractions. These observations demonstrate that miRNAs are distributed differentially in organelles and may re-distribute between organelles and the cytosol in response to cellular stress and metabolic demands.
    Keywords:  Mitochondria-associated ER membrane; Neurodegeneration; Subcellular; Traumatic brain injury; miR-146a; microRNA
    DOI:  https://doi.org/10.1007/s12035-020-01937-y
  12. J Appl Physiol (1985). 2020 May 28.
    Hanson ED, Betik AC, Timpani CA, Tarle J, Zhang X, Hayes A.
      Androgen deprivation therapy (ADT) decreases muscle mass, force, and physical activity levels but it is unclear if disuse atrophy and testosterone suppression are additive. Additionally, conflicting reports exist on load-mediated hypertrophy during ADT and if protein supplementation offsets these deficits. This study sought to determine the role of testosterone suppression and a high protein diet on 1) immobilization-induced atrophy and 2) muscle regrowth during reloading. 8-week old male Fischer 344 rats underwent a sham, castration (ORX) or castration surgery and a high casein diet supplemented with BCAA (ORX+CAS/AA) followed by 10 days of unilateral immobilization (IMM) and 0, 6 or 14 days of reloading. With IMM, body mass gains were ~8% greater than ORX and ORX+CAS/AA that increased to 15% during reloading (both p<0.01). IMM reduced muscle mass by 11-34% (all p<0.01) and extensor digitorum longus and soleus (SOL) force by 21% and 49% (both p<0.01), respectively, with no group differences. During reloading, castration reduced gastrocnemius (~12%) at 6d and SOL mass (~20%) and SOL force recovery (~46%) at 14d relative to Sham (all p<0.05). Specific force reduced castration deficits, indicating muscle atrophy was a key contributor. IMM decreased SOL cross-sectional area by 30.3% (p<0.001) with a trend for reduced regrowth in ORX and ORX+CAS/AA following reloading (p=0.083). Castration did not exacerbate disuse atrophy but may impair recovery of muscle function with no benefit from a CAS/AA diet during reloading. Examining functional outcomes in addition to muscle mass during dietary interventions provide novel insights into muscle regrowth during ADT.
    Keywords:  Testosterone; androgen deprivation therapy; muscle atrophy; muscle hypertrophy; muscle strength
    DOI:  https://doi.org/10.1152/japplphysiol.00752.2019
  13. Aging Cell. 2020 May 28. e13135
    Hinkley JM, Cornnell HH, Standley RA, Chen EY, Narain NR, Greenwood BP, Bussberg V, Tolstikov VV, Kiebish MA, Yi F, Vega RB, Goodpaster BH, Coen PM.
      The loss of skeletal muscle mass and function with age (sarcopenia) is a critical healthcare challenge for older adults. 31-phosphorus magnetic resonance spectroscopy (31 P-MRS) is a powerful tool used to evaluate phosphorus metabolite levels in muscle. Here, we sought to determine which phosphorus metabolites were linked with reduced muscle mass and function in older adults. This investigation was conducted across two separate studies. Resting phosphorus metabolites in skeletal muscle were examined by 31 P-MRS. In the first study, fifty-five older adults with obesity were enrolled and we found that resting phosphocreatine (PCr) was positively associated with muscle volume and knee extensor peak power, while a phosphodiester peak (PDE2) was negatively related to these variables. In the second study, we examined well-phenotyped older adults that were classified as nonsarcopenic or sarcopenic based on sex-specific criteria described by the European Working Group on Sarcopenia in Older People. PCr content was lower in muscle from older adults with sarcopenia compared to controls, while PDE2 was elevated. Percutaneous biopsy specimens of the vastus lateralis were obtained for metabolomic and lipidomic analyses. Lower PCr was related to higher muscle creatine. PDE2 was associated with glycerol-phosphoethanolamine levels, a putative marker of phospholipid membrane damage. Lipidomic analyses revealed that the major phospholipids, (phosphatidylcholine, phosphatidylethanolamine, and phosphatidylglycerol) were elevated in sarcopenic muscle and were inversely related to muscle volume and peak power. These data suggest phosphorus metabolites and phospholipids are associated with the loss of skeletal muscle mass and function in older adults.
    Keywords:  aging; muscle volume; peak power; phosphatidylcholine; phosphatidylethanolamine; phosphodiester
    DOI:  https://doi.org/10.1111/acel.13135
  14. Geroscience. 2020 May 26.
    Jang YC, Rodriguez K, Lustgarten MS, Muller FL, Bhattacharya A, Pierce A, Choi JJ, Lee NH, Chaudhuri A, Richardson AG, Van Remmen H.
      The maintenance of skeletal muscle mass depends on the overall balance between the rates of protein synthesis and degradation. Thus, age-related muscle atrophy and function, commonly known as sarcopenia, may result from decreased protein synthesis, increased proteolysis, or simultaneous changes in both processes governed by complex multifactorial mechanisms. Growing evidence implicates oxidative stress and reactive oxygen species (ROS) as an essential regulator of proteolysis. Our previous studies have shown that genetic deletion of CuZn superoxide dismutase (CuZnSOD, Sod1) in mice leads to elevated oxidative stress, muscle atrophy and weakness, and an acceleration in age-related phenotypes associated with sarcopenia. The goal of this study is to determine whether oxidative stress directly influences the acceleration of proteolysis in skeletal muscle of Sod1-/- mice as a function of age. Compared to control, Sod1-/- muscle showed a significant elevation in protein carbonyls and 3-nitrotyrosine levels, suggesting high oxidative and nitrosative protein modifications were present. In addition, age-dependent muscle atrophy in Sod1-/- muscle was accompanied by an upregulation of the cysteine proteases, calpain, and caspase-3, which are known to play a key role in the initial breakdown of sarcomeres during atrophic conditions. Furthermore, an increase in oxidative stress-induced muscle atrophy was also strongly coupled with simultaneous activation of two major proteolytic systems, the ubiquitin-proteasome and lysosomal autophagy pathways. Collectively, our data suggest that chronic oxidative stress in Sod1-/- mice accelerates age-dependent muscle atrophy by enhancing coordinated activation of the proteolytic systems, thereby resulting in overall protein degradation.
    Keywords:  Autophagy; Muscle atrophy; Protein oxidation; Proteolysis; Sarcopenia; Ubiquitin proteasome
    DOI:  https://doi.org/10.1007/s11357-020-00200-5
  15. EMBO Rep. 2020 May 24. e50094
    Bar-Ziv R, Bolas T, Dillin A.
      Multicellular organisms are complex biological systems, composed of specialized tissues that require coordination of the metabolic and fitness state of each component. In the cells composing the tissues, one central organelle is the mitochondrion, a compartment essential for many energetic and fundamental biological processes. Beyond serving these functions, mitochondria have emerged as signaling hubs in biological systems, capable of inducing changes to the cell they are in, to cells in distal tissues through secreted factors, and to overall animal physiology. Here, we describe our current understanding of these communication mechanisms in the context of mitochondrial stress. We focus on cellular mechanisms that deal with perturbations to the mitochondrial proteome and outline recent advances in understanding how local perturbations can affect distal tissues and animal physiology in model organisms. Finally, we discuss recent findings of these responses associated with metabolic and age-associated diseases in mammalian systems, and how they may be employed as diagnostic and therapeutic tools.
    Keywords:  aging; mitochondria; stress
    DOI:  https://doi.org/10.15252/embr.202050094
  16. Int J Mol Sci. 2020 May 23. pii: E3691. [Epub ahead of print]21(10):
    Deval C, Calonne J, Coudy-Gandilhon C, Vazeille E, Bechet D, Polge C, Taillandier D, Attaix D, Combaret L.
      Mitochondria alterations are a classical feature of muscle immobilization, and autophagy is required for the elimination of deficient mitochondria (mitophagy) and the maintenance of muscle mass. We focused on the regulation of mitochondrial quality control during immobilization and remobilization in rat gastrocnemius (GA) and tibialis anterior (TA) muscles, which have very different atrophy and recovery kinetics. We studied mitochondrial biogenesis, dynamic, movement along microtubules, and addressing to autophagy. Our data indicated that mitochondria quality control adapted differently to immobilization and remobilization in GA and TA muscles. Data showed i) a disruption of mitochondria dynamic that occurred earlier in the immobilized TA, ii) an overriding role of mitophagy that involved Parkin-dependent and/or independent processes during immobilization in the GA and during remobilization in the TA, and iii) increased mitochondria biogenesis during remobilization in both muscles. This strongly emphasized the need to consider several muscle groups to study the mechanisms involved in muscle atrophy and their ability to recover, in order to provide broad and/or specific clues for the development of strategies to maintain muscle mass and improve the health and quality of life of patients.
    Keywords:  immobilization; microtubules; mitophagy; physical inactivity; recovery; skeletal muscle
    DOI:  https://doi.org/10.3390/ijms21103691
  17. Elife. 2020 May 28. pii: e49178. [Epub ahead of print]9
    Mick E, Titov DV, Skinner OS, Sharma R, Jourdain AA, Mootha VK.
      Mitochondrial dysfunction is associated with activation of the integrated stress response (ISR) but the underlying triggers remain unclear. We systematically combined acute mitochondrial inhibitors with genetic tools for compartment-specific NADH oxidation to trace mechanisms linking different forms of mitochondrial dysfunction to the ISR in proliferating mouse myoblasts and in differentiated myotubes. In myoblasts, we find that impaired NADH oxidation upon electron transport chain (ETC) inhibition depletes asparagine, activating the ISR via the eIF2α kinase GCN2. In myotubes, however, impaired NADH oxidation following ETC inhibition neither depletes asparagine nor activates the ISR, reflecting an altered metabolic state. ATP synthase inhibition in myotubes triggers the ISR via a distinct mechanism related to mitochondrial inner-membrane hyperpolarization. Our work dispels the notion of a universal path linking mitochondrial dysfunction to the ISR, instead revealing multiple paths that depend both on the nature of the mitochondrial defect and on the metabolic state of the cell.
    Keywords:  ATF4; GCN2; genetics; genomics; human; human biology; integrated stress response; medicine; metabolism; mitochondria; mouse; p53
    DOI:  https://doi.org/10.7554/eLife.49178
  18. FASEB J. 2020 May 28.
    Nederveen JP, Joanisse S, Thomas ACQ, Snijders T, Manta K, Bell KE, Phillips SM, Kumbhare D, Parise G.
      Skeletal muscle satellite cell (SC) function and responsiveness is regulated, in part, through interactions within the niche, in which they reside. Evidence suggests that structural changes occur in the SC niche as a function of aging. In the present study, we investigated the impact of aging on SC niche properties. Muscle biopsies were obtained from the vastus lateralis of healthy young (YM; 21 ± 1 yr; n = 10) and older men (OM; 68 ± 1 yr; n = 16) at rest. A separate group of OM performed a single bout of resistance exercise and additional muscle biopsies were taken 24 and 48 hours post-exercise; this was performed before and following 12 wks of combined exercise training (OM-Ex; 73 ± 1; n = 24). Muscle SC niche measurements were assessed using high resolution immunofluorescent confocal microscopy. Type II SC niche laminin thickness was greater in OM (1.86 ± 0.06 µm) as compared to YM (1.55 ± 0.09 µm, P < .05). The percentage of type II-associated SC that were completely surrounded by laminin was greater in OM (13.6%±4.2%) as compared to YM (3.5%±1.5%; P < .05). In non-surrounded SC, the proportion of active MyoD+ /Pax7+ SC were higher compared to surrounded SC (P < .05) following a single bout of exercise. This "incarceration" of the SC niche by laminin appears with aging and may inhibit SC activation in response to exercise.
    Keywords:  Pax7; basal lamina; muscle stem cells; satellite cell niche
    DOI:  https://doi.org/10.1096/fj.201900787R
  19. Am J Clin Nutr. 2020 May 29. pii: nqaa136. [Epub ahead of print]
    Kilroe SP, Fulford J, Jackman S, Holwerda A, Gijsen A, van Loon L, Wall BT.
      BACKGROUND: Short-term (<1 wk) muscle disuse lowers daily myofibrillar protein synthesis (MyoPS) rates resulting in muscle mass loss. The understanding of how daily dietary protein intake influences such muscle deconditioning requires further investigation.OBJECTIVES: To assess the influence of graded dietary protein intakes on daily MyoPS rates and the loss of muscle mass during 3 d of disuse.
    METHODS: Thirty-three healthy young men (aged 22 ± 1 y; BMI = 23 ± 1 kg/m2) initially consumed the same standardized diet for 5 d, providing 1.6 g protein/kg body mass/d. Thereafter, participants underwent a 3-d period of unilateral leg immobilization during which they were randomly assigned to 1 of 3 eucaloric diets containing relatively high, low, or no protein (HIGH: 1.6, LOW: 0.5, NO: 0.15 g protein/kg/d; n = 11 per group). One day prior to immobilization participants ingested 400 mL deuterated water (D2O) with 50-mL doses consumed daily thereafter. Prior to and immediately after immobilization upper leg bilateral MRI scans and vastus lateralis muscle biopsies were performed to measure quadriceps muscle volume and daily MyoPS rates, respectively.
    RESULTS: Quadriceps muscle volume of the control legs remained unchanged throughout the experiment (P > 0.05). Immobilization led to 2.3 ± 0.4%, 2.7 ± 0.2%, and 2.0 ± 0.4% decreases in quadriceps muscle volume (P < 0.05) of the immobilized leg in the HIGH, LOW, and NO groups (P < 0.05), respectively, with no significant differences between groups (P > 0.05). D2O ingestion resulted in comparable plasma free [2H]-alanine enrichments during immobilization (∼2.5 mole percentage excess) across groups (P > 0.05). Daily MyoPS rates during immobilization were 30 ± 2% (HIGH), 26 ± 3% (LOW), and 27 ± 2% (NO) lower in the immobilized compared with the control leg, with no significant differences between groups (P > 0.05).
    CONCLUSIONS: Three days of muscle disuse induces considerable declines in muscle mass and daily MyoPS rates. However, daily protein intake does not modulate any of these muscle deconditioning responses.Clinical trial registry number: NCT03797781.
    Keywords:  atrophy; dietary protein; immobilization; muscle protein synthesis; skeletal muscle
    DOI:  https://doi.org/10.1093/ajcn/nqaa136