bims-misrem 2020-09-06 papers

bims-misrem

Biomed News

on Mitochondria and sarcoplasmic reticulum in muscle mass

Issue of 2020–09–06
ten papers selected by
Rafael Antonio Casuso Pérez, University of Granada

A Cell-Autonomous Signature of Dysregulated Protein Phosphorylation Underlies Muscle Insulin Resistance in Type 2 Diabetes.
Extramyocellular interleukin-6 influences skeletal muscle mitochondrial physiology through canonical JAK/STAT signaling pathways.
Do not neglect the role of circadian rhythm in muscle atrophy.
Graded reductions in pre-exercise glycogen concentration do not augment exercise-induced nuclear AMPK and PGC-1α protein content in human muscle.
A High-Density Human Mitochondrial Proximity Interaction Network.
Mitonuclear Interactions in the Maintenance of Mitochondrial Integrity.
Small molecule strategies to harness the unfolded protein response: where do we go from here?
Molecular Connectivity of Mitochondrial Gene Expression and OXPHOS Biogenesis.
The Body Region Specificity in Murine Models of Muscle Regeneration and Atrophy.
How the mitochondrial calcium uniporter complex (MCUcx) works.

Cell Metab. 2020 Aug 31. pii: S1550-4131(20)30420-4. [Epub ahead of print]

A Cell-Autonomous Signature of Dysregulated Protein Phosphorylation Underlies Muscle Insulin Resistance in Type 2 Diabetes.

Thiago M Batista, Ashok Kumar Jayavelu, Nicolai J Wewer Albrechtsen, Salvatore Iovino, Jasmin Lebastchi, Hui Pan, Jonathan M Dreyfuss, Anna Krook, Juleen R Zierath, Matthias Mann, C Ronald Kahn.

  Skeletal muscle insulin resistance is the earliest defect in type 2 diabetes (T2D), preceding and predicting disease development. To what extent this reflects a primary defect or is secondary to tissue cross talk due to changes in hormones or circulating metabolites is unknown. To address this question, we have developed an in vitro disease-in-a-dish model using iPS cells from T2D patients differentiated into myoblasts (iMyos). We find that T2D iMyos in culture exhibit multiple defects mirroring human disease, including an altered insulin signaling, decreased insulin-stimulated glucose uptake, and reduced mitochondrial oxidation. More strikingly, global phosphoproteomic analysis reveals a multidimensional network of signaling defects in T2D iMyos going beyond the canonical insulin-signaling cascade, including proteins involved in regulation of Rho GTPases, mRNA splicing and/or processing, vesicular trafficking, gene transcription, and chromatin remodeling. These cell-autonomous defects and the dysregulated network of protein phosphorylation reveal a new dimension in the cellular mechanisms underlying the fundamental defects in T2D.

Keywords:  chromatin remodeling; glucose transport; iPSC; insulin resistance; mRNA splicing; mitochondrial oxidation; phosphoproteomics; skeletal muscle; type 2 diabetes; vesicle trafficking

DOI:  https://doi.org/10.1016/j.cmet.2020.08.007
FASEB J. 2020 Sep 03.

Extramyocellular interleukin-6 influences skeletal muscle mitochondrial physiology through canonical JAK/STAT signaling pathways.

Hinnah Abid, Zachary C Ryan, Philippe Delmotte, Gary C Sieck, Ian R Lanza.

  Interleukin-6 (IL-6) is a pleiotropic cytokine that has been shown to be produced acutely by skeletal muscle in response to exercise, yet chronically elevated with obesity and aging. The mechanisms by which IL-6 influences skeletal muscle mitochondria acutely and chronically are unclear. To better understand the influence of extramyocellular IL-6 on skeletal muscle mitochondrial physiology, we treated differentiated myotubes with exogenous IL-6 to evaluate the dose- and duration-dependent effects of IL-6 on salient aspects of mitochondrial biology and the role of canonical IL-6 signaling in muscle cells. Acute exposure of myotubes to IL-6 increased the mitochondrial reactive oxygen species (mtROS) production and oxygen consumption rates (JO2 ) in a manner that was dependent on activation of the JAK/STAT pathway. Furthermore, STAT3 activation by IL-6 was partly attenuated by MitoQ, a mitochondrial-targeted antioxidant, suggesting that mtROS potentiates STAT3 signaling in skeletal muscle in response to IL-6 exposure. In concert with effects on mitochondrial physiology, acute IL-6 exposure induced several mitochondrial adaptations, consistent with the stress-induced mitochondrial hyperfusion. Exposure of myotubes to chronically elevated IL-6 further increased mtROS with eventual loss of respiratory capacity. These data provide new evidence supporting the interplay between cytokine signaling and mitochondrial physiology in skeletal muscle.

Keywords:  STAT3; interleukin-6; mitochondria; reactive oxygen species; skeletal muscle

DOI:  https://doi.org/10.1096/fj.202000965RR
Ageing Res Rev. 2020 Aug 31. pii: S1568-1637(20)30290-7. [Epub ahead of print] 101155

Do not neglect the role of circadian rhythm in muscle atrophy.

Hu Zhang, Jiling Liang, Ning Chen.

  In addition to its role in movement, human skeletal muscle also plays important roles in physiological activities related to metabolism and the endocrine system. Aging and disease onset and progression can induce the reduction of skeletal muscle mass and function, thereby exacerbating skeletal muscle atrophy. Recent studies have confirmed that skeletal muscle atrophy is mainly controlled by the balance between protein synthesis and degradation, the activation of satellite cells, and mitochondrial quality in skeletal muscle. Circadian rhythm is an internal rhythm related to an organism's adaptation to light-dark or day-night cycles of the planet, and consists of a core biological clock and a peripheral biological clock. Skeletal muscle, as the most abundant tissue in the human body, is an essential part of the peripheral biological clock in humans. Increasing evidence has confirmed that maintaining a normal circadian rhythm can be beneficial for increasing protein content, improving mitochondrial quality, and stimulating regeneration and repairing of cells in skeletal muscle to prevent or alleviate skeletal muscle atrophy. In this review, we summarize the roles and underlying mechanisms of circadian rhythm in delaying skeletal muscle atrophy, which will provide a theoretical reference for incorporating aspects of circadian rhythm to the prevention and treatment of skeletal muscle atrophy.

Keywords:  circadian rhythm; mitochondrial; muscle atrophy; muscle satellite cell; protein synthesis and degradation; quality control

DOI:  https://doi.org/10.1016/j.arr.2020.101155
Exp Physiol. 2020 Aug 30.

Graded reductions in pre-exercise glycogen concentration do not augment exercise-induced nuclear AMPK and PGC-1α protein content in human muscle.

Mark A Hearris, Daniel J Owens, Juliette A Strauss, Sam O Shepherd, Adam P Sharples, James P Morton, Julien B Louis.

   NEW FINDINGS: What is the central question of this study? What is the absolute level of pre-exercise glycogen concentration required to augment the exercise-induced signalling response regulating mitochondrial biogenesis? What is the main finding and its importance? Commencing high-intensity endurance exercise with reduced pre-exercise muscle glycogen concentrations confers no additional benefit to the early signalling responses that regulate mitochondrial biogenesis.
ABSTRACT: We examined the effects of graded muscle glycogen on the subcellular location of AMPK and PGC-1α protein content and mRNA expression of genes associated with the regulation of mitochondrial biogenesis and substrate utilisation in human skeletal muscle. In a repeated measures design, eight trained male cyclists completed acute high-intensity interval (HIT) cycling (8 × 5 min at 80% peak power output) with graded concentrations of pre-exercise muscle glycogen. Following initial glycogen depleting exercise, subjects ingested 2 g kg-1 (L-CHO), 6 g kg-1 (M-CHO) or 14 g kg-1 (H-CHO) of carbohydrate during a 36 h period, such that exercise was commenced with graded (P < 0.05) muscle glycogen concentrations (H-CHO; 531 ± 83, M-CHO; 332 ± 88, L-CHO; 208 ± 79 mmol·kg-1 dw). Exercise depleted muscle glycogen to < 300 mmol·kg-1 dw in all trials (H-CHO; 270 ± 88, M-CHO; 173 ± 74, L-CHO; 100 ± 42 mmol·kg-1 dw) and induced comparable increases in nuclear AMPK protein content (∼2 fold) and PGC-1α (∼5 fold), p53 (∼1.5 fold) and CPT-1 (∼2 fold) mRNA between trials (all P < 0.05). The magnitude of increase in PGC-1α mRNA was also positively correlated with post-exercise glycogen concentration (P < 0.05). In contrast, exercise nor carbohydrate availability affected the subcellular location of PGC-1α protein or PPAR, SCO2, SIRT1, DRP1, MFN2 or CD36 mRNA. Using a sleep-low, train-low model with a high-intensity endurance exercise stimulus, we conclude that pre-exercise muscle glycogen does not modulate skeletal muscle cell signalling. This article is protected by copyright. All rights reserved.

Keywords:  CHO restriction; train-low; vastus lateralis

DOI:  https://doi.org/10.1113/EP088866
Cell Metab. 2020 Sep 01. pii: S1550-4131(20)30412-5. [Epub ahead of print]32(3): 479-497.e9

A High-Density Human Mitochondrial Proximity Interaction Network.

Hana Antonicka, Zhen-Yuan Lin, Alexandre Janer, Mari J Aaltonen, Woranontee Weraarpachai, Anne-Claude Gingras, Eric A Shoubridge.

  We used BioID, a proximity-dependent biotinylation assay with 100 mitochondrial baits from all mitochondrial sub-compartments, to create a high-resolution human mitochondrial proximity interaction network. We identified 1,465 proteins, producing 15,626 unique high-confidence proximity interactions. Of these, 528 proteins were previously annotated as mitochondrial, nearly half of the mitochondrial proteome defined by Mitocarta 2.0. Bait-bait analysis showed a clear separation of mitochondrial compartments, and correlation analysis among preys across all baits allowed us to identify functional clusters involved in diverse mitochondrial functions and to assign uncharacterized proteins to specific modules. We demonstrate that this analysis can assign isoforms of the same mitochondrial protein to different mitochondrial sub-compartments and show that some proteins may have multiple cellular locations. Outer membrane baits showed specific proximity interactions with cytosolic proteins and proteins in other organellar membranes, suggesting specialization of proteins responsible for contact site formation between mitochondria and individual organelles.

Keywords:  BioID proximity interactions; functional modules; mitochondrial protein proximity map; mitochondrial translation initiation; organellar contact sites; sub-mitochondrial organization

DOI:  https://doi.org/10.1016/j.cmet.2020.07.017
Life (Basel). 2020 Aug 31. pii: E173. [Epub ahead of print]10(9):

Mitonuclear Interactions in the Maintenance of Mitochondrial Integrity.

Panagiotis Karakaidos, Theodoros Rampias.

  In eukaryotic cells, mitochondria originated in an α-proteobacterial endosymbiont. Although these organelles harbor their own genome, the large majority of genes, originally encoded in the endosymbiont, were either lost or transferred to the nucleus. As a consequence, mitochondria have become semi-autonomous and most of their processes require the import of nuclear-encoded components to be functional. Therefore, the mitochondrial-specific translation has evolved to be coordinated by mitonuclear interactions to respond to the energetic demands of the cell, acquiring unique and mosaic features. However, mitochondrial-DNA-encoded genes are essential for the assembly of the respiratory chain complexes. Impaired mitochondrial function due to oxidative damage and mutations has been associated with numerous human pathologies, the aging process, and cancer. In this review, we highlight the unique features of mitochondrial protein synthesis and provide a comprehensive insight into the mitonuclear crosstalk and its co-evolution, as well as the vulnerabilities of the animal mitochondrial genome.

Keywords:  mitochondrial diseases; mitochondrion genetic code; mitonuclear coevolution; mt-DNA repair; translational fidelity

DOI:  https://doi.org/10.3390/life10090173
J Biol Chem. 2020 Sep 04. pii: jbc.REV120.010218. [Epub ahead of print]

Small molecule strategies to harness the unfolded protein response: where do we go from here?

Julia M D Grandjean, R Luke Wiseman.

  The unfolded protein response (UPR) plays a central role in regulating endoplasmic reticulum (ER) and global cellular physiology in response to pathologic ER stress. The UPR is comprised of three signaling pathways activated downstream of the ER membrane proteins IRE1, ATF6, and PERK. Once activated, these proteins initiate transcriptional and translational signaling that functions to alleviate ER stress, adapt cellular physiology, and dictate cell fate. Imbalances in UPR signaling are implicated in the pathogenesis of numerous, etiologically-diverse diseases including many neurodegenerative diseases, protein misfolding diseases, diabetes, ischemic disorders, and cancer. This has led to significant interest in establishing pharmacologic strategies to selectively modulate IRE1, ATF6, or PERK signaling to both ameliorate pathologic imbalances in UPR signaling implicated in these different diseases, and to define the importance of the UPR in diverse cellular and organismal contexts. Recently, there has been significant progress in the identification and characterization of UPR modulating compounds, providing new opportunities to probe the pathologic and potentially therapeutic implications of UPR signaling in human disease. Here, we describe currently available UPR modulating compounds, specifically highlighting the strategies used for their discovery and specific advantages and disadvantages in their application for probing UPR function. Furthermore, we discuss lessons learned from the application of these compounds in cellular and in vivo models to identify favorable compound properties that can help drive the further translational development of selective UPR modulators for human disease.

Keywords:  endoplasmic reticulum stress (ER stress); proteostasis; small molecule; stress response; unfolded protein response (UPR)

DOI:  https://doi.org/10.1074/jbc.REV120.010218
Mol Cell. 2020 Aug 04. pii: S1097-2765(20)30515-3. [Epub ahead of print]

Molecular Connectivity of Mitochondrial Gene Expression and OXPHOS Biogenesis.

Abeer Prakash Singh, Roger Salvatori, Wasim Aftab, Andreas Aufschnaiter, Andreas Carlström, Ignasi Forne, Axel Imhof, Martin Ott.

  Mitochondria contain their own gene expression systems, including membrane-bound ribosomes dedicated to synthesizing a few hydrophobic subunits of the oxidative phosphorylation (OXPHOS) complexes. We used a proximity-dependent biotinylation technique, BioID, coupled with mass spectrometry to delineate in baker's yeast a comprehensive network of factors involved in biogenesis of mitochondrial encoded proteins. This mitochondrial gene expression network (MiGENet) encompasses proteins involved in transcription, RNA processing, translation, or protein biogenesis. Our analyses indicate the spatial organization of these processes, thereby revealing basic mechanistic principles and the proteins populating strategically important sites. For example, newly synthesized proteins are directly handed over to ribosomal tunnel exit-bound factors that mediate membrane insertion, co-factor acquisition, or their mounting into OXPHOS complexes in a special early assembly hub. Collectively, the data reveal the connectivity of mitochondrial gene expression, reflecting a unique tailoring of the mitochondrial gene expression system.

Keywords:  assembly; co-factor acquisition; gene expression; mitochondria; network; proximity interactions; respiratory chain; ribosome; translation; tunnel exit

DOI:  https://doi.org/10.1016/j.molcel.2020.07.024
Acta Physiol (Oxf). 2020 Sep 02. e13553

The Body Region Specificity in Murine Models of Muscle Regeneration and Atrophy.

Kiyoshi Yoshioka, Yasuo Kitajima, Daiki Seko, Yoshifumi Tsuchiya, Yusuke Ono.

   AIM: Skeletal muscles are distributed throughout the body, presenting a variety of sizes, shapes, and functions. Here, we examined whether muscle regeneration and atrophy occurred homogeneously throughout the body in mouse models.
METHODS: Acute muscle regeneration was induced by a single intramuscular injection of cardiotoxin in adult mice. Chronic muscle regeneration was assessed in mdx mice. Muscle atrophy in different muscles was evaluated by cancer-cachexia, aging, and castration mouse models.
RESULTS: We found that, in the cardiotoxin-injected acute muscle injury model, head muscles slowly regenerated, while limb muscles exhibited a rapid regeneration and even overgrowth. This overgrowth was also observed in limb muscles alone (but not in head muscles) in mdx mice as chronic injury models. We described the body-region specific decline in the muscle mass in muscle atrophy models: cancer cachexia-induced, aged, and castrated mice. The positional identities, including gene expression profiles and hormone sensitivity, were robustly preserved in the ectopically engrafted satellite cell-derived muscles in the castrated model.
CONCLUSION: Our results indicate that positional identities in muscles should be considered for the development of efficient regenerative therapies for muscle weakness, such as muscular dystrophy and age-related sarcopenia.

Keywords:  Aging; Cancer cachexia; Castration; Heterogeneity; Muscle atrophy; Positional memory; Skeletal Muscle

DOI:  https://doi.org/10.1111/apha.13553
Proc Natl Acad Sci U S A. 2020 Sep 02. pii: 202015886. [Epub ahead of print]

How the mitochondrial calcium uniporter complex (MCUcx) works.

Liron Boyman, W Jonathan Lederer.

DOI: https://doi.org/10.1073/pnas.2015886117