bims-misrem 2021-01-31 papers

bims-misrem

Biomed News

on Mitochondria and sarcoplasmic reticulum in muscle mass

Issue of 2021–01–31
eleven papers selected by
Rafael Antonio Casuso Pérez, University of Granada

A guide to understanding endoplasmic reticulum stress in metabolic disorders.
Mitochondria Homeostasis and Oxidant/Antioxidant Balance in Skeletal Muscle-Do Myokines Play a Role?
Nicotinamide riboside supplementation does not alter whole-body or skeletal muscle metabolic responses to a single bout of endurance exercise.
From mitochondria to sarcopenia: Role of inflammaging and RAGE-ligand axis implication.
Disturbed intramitochondrial phosphatidic acid transport impairs cellular stress signaling.
Low responders to endurance training exhibit impaired hypertrophy and divergent biological process responses in rat skeletal muscle.
How do exercise training variables stimulate processes related to mitochondrial biogenesis in slow and fast trout muscle fibres?
Can High-Intensity Interval Training Promote Skeletal Muscle Anabolism?
Structural basis for a complex I mutation that blocks pathological ROS production.
Aerobic exercise improves mitochondrial function in sarcopenia mice through Sestrin2 in an AMPKα2-dependent manner.
ER-Phagy, ER Homeostasis, and ER Quality Control: Implications for Disease.

Mol Metab. 2021 Jan 20. pii: S2212-8778(21)00009-0. [Epub ahead of print] 101169

A guide to understanding endoplasmic reticulum stress in metabolic disorders.

Imke L Lemmer, Nienke Willemsen, Nazia Hilal, Alexander Bartelt.

   BACKGROUND: The global rise of metabolic disorders, such as obesity, diabetes type 2 and cardiovascular disease, demands a thorough molecular understanding of the cellular mechanisms that govern health or disease. The endoplasmic reticulum (ER) is a key organelle for cellular function and metabolic adaptation and, therefore, disturbed ER function, "ER stress", is a key feature of metabolic disorders.
SCOPE OF REVIEW: As ER stress remains an ill-defined phenomenon, this review provides a general guide to understanding the nature, aetiology and consequences of ER stress in metabolic disorders. We define ER stress by its type of stressor, which is driven by proteotoxicity, lipotoxicity, and/or glucotoxicity. We discuss the implications of ER stress in metabolic disorders by reviewing evidence implicating ER phenotypes and organelle communication, protein quality control, calcium homeostasis, lipid and carbohydrate metabolism, and inflammation as key mechanisms in the development of ER stress and metabolic dysfunction.
MAJOR CONCLUSIONS: In mammalian biology, ER is a phenotypically and functionally diverse platform for nutrient sensing, which is critical for cell-type specific metabolic control by e.g. hepatocytes, adipocytes, muscle cells, and neurons. In these cells, ER stress is a distinct, transient state of functional imbalance, which is usually resolved by the activation of adaptive programs such as the unfolded protein response (UPR), ER-associated protein degradation (ERAD), or autophagy. However, challenges to proteostasis also impact lipid and glucose metabolism and vice versa. In the ER, both sensing and adaptive measures are integrated and failure of the ER to adapt leads to aberrant metabolism, organelle dysfunction, insulin resistance, and inflammation. In conclusion, the ER is intricately linked to a wide spectrum of cellular functions and is a critical component in maintaining and restoring metabolic health.

Keywords:  ERAD; NFE2L1; Obesity; UPR; UPS; autophagy; calcium homeostasis; diabetes; endoplasmic reticulum; glucotoxicity; inflammation; lipid metabolism; lipotoxicity; proteostasis; proteotoxicity

DOI:  https://doi.org/10.1016/j.molmet.2021.101169
Antioxidants (Basel). 2021 Jan 27. pii: 179. [Epub ahead of print]10(2):

Mitochondria Homeostasis and Oxidant/Antioxidant Balance in Skeletal Muscle-Do Myokines Play a Role?

Brian Pak Shing Pang, Wing Suen Chan, Chi Bun Chan.

  Mitochondria are the cellular powerhouses that generate adenosine triphosphate (ATP) to substantiate various biochemical activities. Instead of being a static intracellular structure, they are dynamic organelles that perform constant structural and functional remodeling in response to different metabolic stresses. In situations that require a high ATP supply, new mitochondria are assembled (mitochondrial biogenesis) or formed by fusing the existing mitochondria (mitochondrial fusion) to maximize the oxidative capacity. On the other hand, nutrient overload may produce detrimental metabolites such as reactive oxidative species (ROS) that wreck the organelle, leading to the split of damaged mitochondria (mitofission) for clearance (mitophagy). These vital processes are tightly regulated by a sophisticated quality control system involving energy sensing, intracellular membrane interaction, autophagy, and proteasomal degradation to optimize the number of healthy mitochondria. The effective mitochondrial surveillance is particularly important to skeletal muscle fitness because of its large tissue mass as well as its high metabolic activities for supporting the intensive myofiber contractility. Indeed, the failure of the mitochondrial quality control system in skeletal muscle is associated with diseases such as insulin resistance, aging, and muscle wasting. While the mitochondrial dynamics in cells are believed to be intrinsically controlled by the energy content and nutrient availability, other upstream regulators such as hormonal signals from distal organs or factors generated by the muscle itself may also play a critical role. It is now clear that skeletal muscle actively participates in systemic energy homeostasis via producing hundreds of myokines. Acting either as autocrine/paracrine or circulating hormones to crosstalk with other organs, these secretory myokines regulate a large number of physiological activities including insulin sensitivity, fuel utilization, cell differentiation, and appetite behavior. In this article, we will review the mechanism of myokines in mitochondrial quality control and ROS balance, and discuss their translational potential.

Keywords:  ROS; aging; exercise; mitochondria; myokine

DOI:  https://doi.org/10.3390/antiox10020179
J Physiol. 2021 Jan 25.

Nicotinamide riboside supplementation does not alter whole-body or skeletal muscle metabolic responses to a single bout of endurance exercise.

Ben Stocks, Stephen P Ashcroft, Sophie Joanisse, Linda C Dansereau, Yen Chin Koay, Yasir S Elhassan, Gareth G Lavery, Lake-Ee Quek, John F O'Sullivan, Ashleigh M Philp, Gareth A Wallis, Andrew Philp.

   KEY POINTS: Acute nicotinamide riboside (NR) supplementation does not alter substrate metabolism at rest, during or in recovery from endurance exercise. NR does not alter NAD+ -sensitive signalling pathways in human skeletal muscle. NR supplementation and acute exercise influence the NAD+ metabolome.
ABSTRACT: Oral supplementation of the NAD+ precursor nicotinamide riboside (NR) has been reported to alter metabolism alongside increasing sirtuin (SIRT) signalling and mitochondrial biogenesis in rodent skeletal muscle. However, whether NR supplementation can elicit a similar response in human skeletal muscle is unclear. This study assessed the effect of 7-day NR supplementation on whole-body metabolism and exercise-induced mitochondrial biogenic signalling in skeletal muscle. Eight male participants (age: 23 ± 4 years, V̇O2peak 46.5 ± 4.4 ml kg-1 min-1 ) received 1 week of NR or cellulose placebo (PLA) supplementation (1000 mg day-1 ). Muscle biopsies were collected from the medial vastus lateralis prior to supplementation and pre-, immediately post- and 3 h post-exercise (1 h of 60% Wmax cycling) performed following the supplementation period. There was no effect of NR supplementation on substrate utilisation at rest or during exercise or on skeletal muscle mitochondrial respiration. Global acetylation, auto-PARylation of poly ADP-ribose polymerase 1 (PARP1), acetylation of Tumour protein 53 (p53)Lys382 and Manganese superoxide dismutase (MnSOD)Lys122 were also unaffected by NR supplementation or exercise. NR supplementation did not increase skeletal muscle NAD+ concentration, but it did increase the concentration of deaminated NAD+ precursors nicotinic acid riboside (NAR) and nicotinic acid mononucleotide (NAM) and methylated nicotinamide breakdown products (Me2PY and Me4PY), demonstrating the skeletal muscle bioavailability of NR supplementation. In summary, 1 week of NR supplementation does not alter whole-body metabolism or skeletal muscle signal transduction pathways implicated in the mitochondrial adaptation to endurance exercise.

Keywords:  NAD+; exercise; metabolism; skeletal muscle

DOI:  https://doi.org/10.1113/JP280825
Exp Gerontol. 2021 Jan 20. pii: S0531-5565(21)00022-X. [Epub ahead of print]146 111247

From mitochondria to sarcopenia: Role of inflammaging and RAGE-ligand axis implication.

Frédéric N Daussin, Eric Boulanger, Steve Lancel.

  Sarcopenia is characterized by a loss of muscle mass and function that reduces mobility, diminishes quality of life, and can lead to fall-related injuries. At the intracellular level, mitochondrial population alterations are considered as key contributors to the complex etiology of sarcopenia. Mitochondrial dysfunctions lead to reactive oxygen species production, altered cellular proteostasis, and promotes inflammation. Interestingly, the receptor for advanced glycation end-products (RAGE) is a pro-inflammatory receptor involved in inflammaging. In this review, after a brief description of sarcopenia, we will describe how mitochondria and the pathways controlling mitochondrial population quality could participate to age-induced muscle mass and force loss. Finally, we will discuss the RAGE-ligand axis during aging and its possible connection with mitochondria to control inflammaging and sarcopenia.

Keywords:  Aging; Inflammaging; Inflammation; Mitochondria; RAGE; Sarcopenia

DOI:  https://doi.org/10.1016/j.exger.2021.111247
J Biol Chem. 2021 Jan 23. pii: S0021-9258(21)00106-X. [Epub ahead of print] 100335

Disturbed intramitochondrial phosphatidic acid transport impairs cellular stress signaling.

Akinori Eiyama, Mari J Aaltonen, Hendrik Nolte, Takashi Tatsuta, Thomas Langer.

  Lipid transfer proteins of the Ups1/PRELID1 family facilitate the transport of phospholipids across the intermembrane space of mitochondria in a lipid-specific manner. Heterodimeric complexes of yeast Ups1/Mdm35 or human PRELID1/TRIAP1 shuttle phosphatidic acid (PA) mainly synthesized in the endoplasmic reticulum (ER) to the inner membrane, where it is converted to cardiolipin (CL), the signature phospholipid of mitochondria. Loss of Ups1/PRELID1 proteins impairs the accumulation of CL and broadly affects mitochondrial structure and function. Unexpectedly and unlike yeast cells lacking the cardiolipin synthase Crd1, Ups1 deficient yeast cells exhibit glycolytic growth defects, pointing to functions of Ups1-mediated PA transfer beyond CL synthesis. Here, we show that the disturbed intramitochondrial transport of PA in ups1Δ cells leads to altered unfolded protein response (UPR) and mTORC1 signaling, independent of disturbances in CL synthesis. The impaired flux of PA into mitochondria is associated with the increased synthesis of phosphatidylcholine (PC) and a reduced phosphatidylethanolamine (PE)/PC ratio in the ER of ups1Δ cells which suppresses the UPR. Moreover, we observed inhibition of TORC1 signaling in these cells. Activation of either UPR by ER protein stress or of TORC1 signaling by disruption of its negative regulator, the SEACIT complex, increased cytosolic protein synthesis and restored glycolytic growth of ups1Δ cells. These results demonstrate that PA influx into mitochondria is required to preserve ER membrane homeostasis and that its disturbance is associated with impaired glycolytic growth and cellular stress signaling.

Keywords:  Mitochondria; PRELID1; TORC1; Ups1; endoplasmic reticulum (ER); lipid transfer; phospholipid; unfolded protein response (UPR); yeast

DOI:  https://doi.org/10.1016/j.jbc.2021.100335
Exp Physiol. 2021 Jan 24.

Low responders to endurance training exhibit impaired hypertrophy and divergent biological process responses in rat skeletal muscle.

Daniel W D West, Thomas M Doering, Jamie-Lee M Thompson, Boris P Budiono, Sarah J Lessard, Lauren G Koch, Steven L Britton, Roland Steck, Nuala M Byrne, Matthew A Brown, Jonathan M Peake, Kevin J Ashton, Vernon G Coffey.

   NEW FINDINGS: What is the central question of this study? The extent to which genetics determines adaptation to endurance versus resistance exercise is unclear. Previously, a divergent selective breeding rat model showed genetic factors play a major role in the response to aerobic training. Here, we asked: do genetic factors that underpin poor adaptation to endurance training affect adaptation to functional overload? What is the main finding and its importance? Our data show that heritable factors in low responders to endurance training generated differential gene expression that was associated with impaired skeletal muscle hypertrophy. A maladaptive genotype to endurance exercise appears to dysregulate biological processes responsible for mediating exercise adaptation, irrespective of the mode of contraction stimulus.
ABSTRACT: Divergent skeletal muscle phenotypes result from chronic resistance-type versus endurance-type contraction, reflecting the principle of training specificity.
AIM: To determine whether there is a common set of genetic factors that influence skeletal muscle adaptation to divergent contractile stimuli.
METHODS: Female rats were obtained from a genetically heterogenous rat population and were selectively bred from high responders to endurance training (HRT) or low responders to endurance training (LRT; n = 6/group; generation 19). Both groups underwent 14-d synergist ablation to induce functional overload of the plantaris muscle prior to comparison to non-overload controls of the same phenotype. RNA sequencing was performed to identify Gene Ontology Biological Processes with differential (LRT vs HRT) gene set enrichment.
RESULTS: Running distance, determined in advance of synergist ablation, increased in response to aerobic training in HRT but not LRT (65 ±26% versus -6 ±18%, mean ± SD, P<0.0001). The hypertrophy response to functional overload was attenuated in LRT versus HRT (20.1 ±5.6% versus 41.6 ±16.1%, P = 0.015). Between-group differences were observed in the magnitude of response of 96 upregulated and 101 downregulated pathways. A further 27 pathways showed contrasting upregulation or downregulation in LRT versus HRT in response to functional overload.
CONCLUSIONS: Low responders to aerobic endurance training were also low responders for compensatory hypertrophy, and attenuated hypertrophy was associated with differential gene set regulation. Our findings suggest that genetic factors that underpin aerobic training maladaptation may also dysregulate the transcriptional regulation of biological processes that contribute to adaptation to mechanical overload. This article is protected by copyright. All rights reserved.

Keywords:  heritable factors; molecular networks; skeletal muscle plasticity; specificity of adaptation

DOI:  https://doi.org/10.1113/EP089301
Exp Physiol. 2021 Jan 29.

How do exercise training variables stimulate processes related to mitochondrial biogenesis in slow and fast trout muscle fibres?

Morgane Pengam, Aline Amérand, Bernard Simon, Anthony Guernec, Manon Inizan, Christine Moisan.

   NEW FINDINGS: Central question: Exercise is known to promote mitochondrial biogenesis in skeletal muscle, but what are the most relevant training protocols to stimulate it? Main finding and its importance: As in mammals, training in rainbow trout affects slow and fast muscle fibres differently. Exercise intensity, relative to volume, duration and frequency, is the most relevant training variable to stimulate the processes related to mitochondrial biogenesis in both red and white muscles. This study offers new insights into muscle fibre type-specific transcription and expression of genes involved in mitochondrial adaptations following training.
ABSTRACT: Exercise is known to be a powerful way to improve health through the stimulation of mitochondrial biogenesis in skeletal muscle, which undergoes cellular and molecular adaptations. One of the current challenges in human is to define the optimal training stimulus to improve muscle performance. Fish are relevant models for exercise training physiology studies mainly because of their distinct slow and fast muscle fibres. Using rainbow trout, we investigated the effects of six different training protocols defined by manipulating specific training variables (such as exercise intensity, volume, duration and frequency), on mRNAs and some proteins related to four subsystems (AMPK-PGC-1α signalling pathway, mitochondrial function, antioxidant defences and lactate dehydrogenase: LDH metabolism) in both red and white muscles (RM and WM, respectively). In both muscles, high intensity exercise stimulated more mRNA types and enzymatic activities related to mitochondrial biogenesis than moderate intensity exercise. For volume, duration and frequency variables, we demonstrated fibre type-specific responses. Indeed, for high intensity interval training (HIIT), RM transcript levels are increased by a low training volume, but WM transcript responses are stimulated by a high training volume. Moreover, transcripts and enzymatic activities related to mitochondria and LDH show that WM tends to develop aerobic metabolism with a high training volume. For transcript stimulation, WM requires a greater duration and frequency of exercise than RM, whereas protein adaptations are efficient with a long training duration and a high frequency in both muscles. This article is protected by copyright. All rights reserved.

Keywords:  exercise training; mitochondria; skeletal muscle

DOI:  https://doi.org/10.1113/EP089231
Sports Med. 2021 Jan 29.

Can High-Intensity Interval Training Promote Skeletal Muscle Anabolism?

Marcus J Callahan, Evelyn B Parr, John A Hawley, Donny M Camera.

Exercise training in combination with optimal nutritional support is an effective strategy to maintain or increase skeletal muscle mass. A single bout of resistance exercise undertaken with adequate protein availability increases rates of muscle protein synthesis and, when repeated over weeks and months, leads to increased muscle fiber size. While resistance-based training is considered the 'gold standard' for promoting muscle hypertrophy, other modes of exercise may be able to promote gains in muscle mass. High-intensity interval training (HIIT) comprises short bouts of exercise at or above the power output/speed that elicits individual maximal aerobic capacity, placing high tensile stress on skeletal muscle, and somewhat resembling the demands of resistance exercise. While HIIT induces rapid increases in skeletal muscle oxidative capacity, the anabolic potential of HIIT for promoting concurrent gains in muscle mass and cardiorespiratory fitness has received less scientific inquiry. In this review, we discuss studies that have determined muscle growth responses after HIIT, with a focus on molecular responses, that provide a rationale for HIIT to be implemented among populations who are susceptible to muscle loss (e.g. middle-aged or older adults) and/or in clinical settings (e.g. pre- or post-surgery).

DOI: https://doi.org/10.1007/s40279-020-01397-3
Nat Commun. 2021 Jan 29. 12(1): 707

Structural basis for a complex I mutation that blocks pathological ROS production.

Zhan Yin, Nils Burger, Duvaraka Kula-Alwar, Dunja Aksentijević, Hannah R Bridges, Hiran A Prag, Daniel N Grba, Carlo Viscomi, Andrew M James, Amin Mottahedin, Thomas Krieg, Michael P Murphy, Judy Hirst.

Mitochondrial complex I is central to the pathological reactive oxygen species (ROS) production that underlies cardiac ischemia-reperfusion (IR) injury. ND6-P25L mice are homoplasmic for a disease-causing mtDNA point mutation encoding the P25L substitution in the ND6 subunit of complex I. The cryo-EM structure of ND6-P25L complex I revealed subtle structural changes that facilitate rapid conversion to the "deactive" state, usually formed only after prolonged inactivity. Despite its tendency to adopt the "deactive" state, the mutant complex is fully active for NADH oxidation, but cannot generate ROS by reverse electron transfer (RET). ND6-P25L mitochondria function normally, except for their lack of RET ROS production, and ND6-P25L mice are protected against cardiac IR injury in vivo. Thus, this single point mutation in complex I, which does not affect oxidative phosphorylation but renders the complex unable to catalyse RET, demonstrates the pathological role of ROS production by RET during IR injury.

DOI: https://doi.org/10.1038/s41467-021-20942-w
J Gerontol A Biol Sci Med Sci. 2021 Jan 29. pii: glab029. [Epub ahead of print]

Aerobic exercise improves mitochondrial function in sarcopenia mice through Sestrin2 in an AMPKα2-dependent manner.

Sujuan Liu, Chunxia Yu, Lingjian Xie, Yanmei Niu, Li Fu.

  Sarcopenia, the age-related loss of skeletal muscle mass and function, contributes to high morbidity and mortality in the elderly population. Regular exercise is necessary to avoid the initiation and progression of sarcopenia, in which the underlying molecular mechanism is still not clear. Our data revealed that outcomes induced by sarcopenia including muscle mass and strength loss, the cross-sectional area of gastrocnemius fibre decrease, chronic inflammation and dysfunctional mitochondria increase were reversed by regulation exercise. Knockout or silencing of Sestrin2 (Sesn2) resulted in imbalanced mitochondrial fusion and fission, mitochondrial biogenesis and mitophagy damage in vivo and in vitro, which was attenuated by aerobic exercise or overexpression Sesn2. Moreover, we found that the effects of Sesn2 on mitochondrial function are dependent on AMP-activated protein kinase α2 (AMPKα2). This study indicates that aerobic exercise alleviates the negative effects resulting from sarcopenia via the Sesn2/AMPKα2 pathway and provides new insights into the molecular mechanism by which the Sesn2/AMPKα2 signalling axis mediates the beneficial impact of exercise on sarcopenia.

Keywords:  AMPKα2; Aerobic exercise; Age-related sarcopenia; Mitochondrial function; Sestrin2

DOI:  https://doi.org/10.1093/gerona/glab029
Trends Biochem Sci. 2021 Jan 25. pii: S0968-0004(20)30325-X. [Epub ahead of print]

ER-Phagy, ER Homeostasis, and ER Quality Control: Implications for Disease.

Susan Ferro-Novick, Fulvio Reggiori, Jeffrey L Brodsky.

  Lysosomal degradation of endoplasmic reticulum (ER) fragments by autophagy, termed ER-phagy or reticulophagy, occurs under normal as well as stress conditions. The recent discovery of multiple ER-phagy receptors has stimulated studies on the roles of ER-phagy. We discuss how the ER-phagy receptors and the cellular components that work with these receptors mediate two important functions: ER homeostasis and ER quality control. We highlight that ER-phagy plays an important role in alleviating ER expansion induced by ER stress, and acts as an alternative disposal pathway for misfolded proteins. We suggest that the latter function explains the emerging connection between ER-phagy and disease. Additional ER-phagy-associated functions and important unanswered questions are also discussed.

Keywords:  autophagy receptor; endoplasmic reticulum; human disease; macro-ER-phagy; micro-ER-phagy; proteostasis; reticulophagy

DOI:  https://doi.org/10.1016/j.tibs.2020.12.013