Oxidative and glycolytic skeletal muscles deploy protective mechanisms to avoid atrophy under pathophysiological iron overload

Journal article


Martin, David, Nay, Kévin, Robin, François, Rebillard, Amélie, Orfila, Luz, Martin, Brice, Leroyer, Patricia, Guggenbuhl, Pascal, Dufresne, Suzanne, Noirez, Philippe, Ropert, Martine, Loréal, Olivier and Derbré, Frédéric. (2022). Oxidative and glycolytic skeletal muscles deploy protective mechanisms to avoid atrophy under pathophysiological iron overload. Journal of Cachexia, Sarcopenia and Muscle. 13(2), pp. 1250-1261. https://doi.org/10.1002/jcsm.12897
AuthorsMartin, David, Nay, Kévin, Robin, François, Rebillard, Amélie, Orfila, Luz, Martin, Brice, Leroyer, Patricia, Guggenbuhl, Pascal, Dufresne, Suzanne, Noirez, Philippe, Ropert, Martine, Loréal, Olivier and Derbré, Frédéric
Abstract

Background
Iron excess has been proposed as an essential factor in skeletal muscle wasting. Studies have reported correlations between muscle iron accumulation and atrophy, either through ageing or by using experimental models of secondary iron overload. However, iron treatments performed in most of these studies induced an extra-pathophysiological iron overload, more representative of intoxication or poisoning. The main objective of this study was to determine the impact of iron excess closer to pathophysiological conditions on structural and metabolic adaptations (i) in differentiated myotubes and (ii) in skeletal muscle exhibiting oxidative (i.e. the soleus) or glycolytic (i.e. the gastrocnemius) metabolic phenotypes.

Methods
The impact of iron excess was assessed in both in vitro and in vivo models. Murine differentiated myotubes were exposed to ferric ammonium citrate (FAC) (i.e. 10 and 50 μM) for the in vitro component. The in vivo model was achieved by a single iron dextran subcutaneous injection (1 g/kg) in mice. Four months after the injection, soleus and gastrocnemius muscles were harvested for analysis.

Results
In vitro, iron exposure caused dose-dependent increases of iron storage protein ferritin (P < 0.01) and dose-dependent decreases of mRNA TfR1 levels (P < 0.001), which support cellular adaptations to iron excess. Extra-physiological iron treatment (50 μM FAC) promoted myotube atrophy (P = 0.018), whereas myotube size remained unchanged under pathophysiological treatment (10 μM FAC). FAC treatments, whatever the doses tested, did not affect the expression of proteolytic markers (i.e. NF-κB, MurF1, and ubiquitinated proteins). In vivo, basal iron content and mRNA TfR1 levels were significantly higher in the soleus compared with the gastrocnemius (+130% and +127%; P < 0.001, respectively), supporting higher iron needs in oxidative skeletal muscle. Iron supplementation induced muscle iron accumulation in the soleus and gastrocnemius muscles (+79%, P < 0.001 and +34%, P = 0.002, respectively), but ferritin protein expression only increased in the gastrocnemius (+36%, P = 0.06). Despite iron accumulation, muscle weight, fibre diameter, and myosin heavy chain distribution remained unchanged in either skeletal muscle.

Conclusions
Together, these data support that under pathophysiological conditions, skeletal muscle can protect itself from the related deleterious effects of excess iron.

Keywordssarcopenia; disuse; typology; myosin heavy chain; mitochondria
Year2022
JournalJournal of Cachexia, Sarcopenia and Muscle
Journal citation13 (2), pp. 1250-1261
PublisherJohn Wiley & Sons Ltd
ISSN2190-5991
Digital Object Identifier (DOI)https://doi.org/10.1002/jcsm.12897
PubMed ID35118832
Scopus EID2-s2.0-85124132301
PubMed Central IDPMC8978014
Open accessPublished as ‘gold’ (paid) open access
Page range1250-1261
FunderSociété Française de Rhumatologie (SFR)
French Centre National d’Etudes Spatiales (CNES)
Publisher's version
License
File Access Level
Open
Output statusPublished
Publication dates
Online03 Feb 2022
Publication process dates
Accepted22 Nov 2021
Deposited26 Sep 2023
Permalink -

https://acuresearchbank.acu.edu.au/item/8zv04/oxidative-and-glycolytic-skeletal-muscles-deploy-protective-mechanisms-to-avoid-atrophy-under-pathophysiological-iron-overload

Download files


Publisher's version
  • 19
    total views
  • 11
    total downloads
  • 1
    views this month
  • 1
    downloads this month
These values are for the period from 19th October 2020, when this repository was created.

Export as

Related outputs

SGC-CAMKK2-1 : A chemical probe for CAMKK2
Wells, Carrow, Liang, Yi, Pulliam, Thomas L., Lin, Chenchu, Awad, Dominik, Eduful, Benjamin, O’Byrne, Sean, Hossain, Mohammad Anwar, Catta-Preta, Carolina Moura Costa, Ramos, Priscila Zonzini, Gileadi, Opher, Gileadi, Carina, Couñago, Rafael M., Stork, Brittany, Langendorf, Christopher G., Nay, Kevin, Oakhill, Jonathan S., Mukherjee, Debarati, Racioppi, Luigi, ... Drewry, David H.. (2023). SGC-CAMKK2-1 : A chemical probe for CAMKK2. Cells. 12(2), p. Article 287. https://doi.org/10.3390/cells12020287
Molecular mechanisms underlying the beneficial effects of exercise on brain function and neurological disorders
Nay, Kévin, Smiles, William J., Kaiser, Jacqueline, McAloon, Luke M., Loh, Kim, Galic, Sandra, Oakhill, Jonathan S., Gundlach, Andrew L. and Scott, John W.. (2021). Molecular mechanisms underlying the beneficial effects of exercise on brain function and neurological disorders. International Journal of Molecular Sciences. 22, p. Article 4052. https://doi.org/10.3390/ijms22084052
Does physical inactivity induce significant changes in human gut microbiota? New answers using the dry immersion hypoactivity model
Jollet, Maxence, Nay, Kevin, Chopard, Angele, Bareille, Marie-Pierre, Beck, Arnaud, Ollendorff, Vincent, Vernus, Barbara, Bonnieu, Anne, Mariadassou, Mahendra, Rué, Olivier, Derbré, Frédéric, Goustard, Bénédicte and Koechlin-Ramonatxo, Christelle. (2021). Does physical inactivity induce significant changes in human gut microbiota? New answers using the dry immersion hypoactivity model. Nutrients. 13(11), p. Article 3865. https://doi.org/10.3390/nu13113865
Hinge binder scaffold hopping identifies potent calcium/calmodulin-dependent protein kinase kinase 2 (CAMKK2) inhibitor chemotypes
Eduful, Benjamin J., O'Byrne, Sean N., Temme, Louisa, Asquith, Christopher R. M., Liang, Yi, Picado, Alfredo, Pilotte, Joseph R., Hossain, Mohammad Anwar, Wells, Carrow I., Zuercher, William J., Catta-Preta, Carolina M.C, Ramos, Priscila, de S. Santiago, André, Counago, Rafael M., Langendorf, Christopher G., Nay, Kevin, Oakhill, Jonathan S., Pulliam, Thomas L., Lin, Chenchu, ... Drewry, David H.. (2021). Hinge binder scaffold hopping identifies potent calcium/calmodulin-dependent protein kinase kinase 2 (CAMKK2) inhibitor chemotypes. Journal of Medicinal Chemistry. 64(15), pp. 10849-10877. https://doi.org/10.1021/acs.jmedchem.0c02274
Intermittent reloading does not prevent reduction in iron availability and hepcidin upregulation caused by hindlimb unloading
Nay, Kévin, Martin, David, Orfila, Luz, Saligaut, Dany, Martin, Brice, Horeau, Mathieu, Cavey, Thibaut, Kenawi, Moussa, Island, Marie-Laure, Ropert, Martine, Loréal, Olivier, Koechlin-Ramonatxo, Christelle and Derbré, Frédéric. (2021). Intermittent reloading does not prevent reduction in iron availability and hepcidin upregulation caused by hindlimb unloading. Experimental Physiology. 106(1), pp. 28-36. https://doi.org/10.1113/EP088339
Simulated microgravity disturbs iron metabolism and distribution in humans : Lessons from dry immersion, an innovative ground-based human model
Nay, Kévin, Koechlin-Ramonatxo, Christelle, Rochdi, Sarah, Island, Marie-Laure, Orfila, Luz, Treffel, Loïc, Bareille, Marie-Pierre, Beck, Arnaud, Gauquelin-Koch, Guillemette, Ropert, Martine, Loréal, Olivier and Derbré, Frédéric. (2020). Simulated microgravity disturbs iron metabolism and distribution in humans : Lessons from dry immersion, an innovative ground-based human model. The FASEB Journal. 34(11), pp. 14920-14929. https://doi.org/10.1096/fj.202001199RR
Gut bacteria are critical for optimal muscle function: A potential link with glucose homeostasis
Nay, Kevin, Jollet, Maxence, Goustard, Benedicte, Baati, Narjes, Vernus, Barbara, Pontones, Maria, Lefeuvre-Orfila, Luz, Bendavid, Claude, Rué, Olivier, Mariadassou, Mahendra, Bonnieu, Anne, Ollendorff, Vincent, Lepage, Patricia, Derbré, Frédéric and Koechlin-Ramonatxo, Christelle. (2019). Gut bacteria are critical for optimal muscle function: A potential link with glucose homeostasis. American Journal of Physiology - Endocrinology and Metabolism. 317(1), pp. 158 - 171. https://doi.org/10.1152/ajpendo.00521.2018
Skeletal muscle ceramides do not contribute to physical-inactivity-induced insulin resistance
Appriou, Zéphyra, Nay, Kevin, Pierre, Nicolas, Saligaut, Dany, Lefeuvre-Orfila, Luz, Martin, Brice, Cavey, Thibault, Ropert, Martine, Loréal, Olivier, Rannou-Bekono, Françoise and Derbré, Frédéric. (2019). Skeletal muscle ceramides do not contribute to physical-inactivity-induced insulin resistance. Applied Physiology, Nutrition and Metabolism. 44(11), pp. 1180 - 1188. https://doi.org/10.1139/apnm-2018-0850
Ceruloplasmin deficiency does not induce macrophagic iron overload: Lessons from a new rat model of hereditary aceruloplasminemia
Kenawi, Moussa, Rouger, Emmanuel, Island, Marie-Laure, Leroyer, Patricia, Robin, François, Rémy, Séverine, Tesson, Laurent, Anegon, Ignacio, Nay, Kevin, Derbré, Frédéric, Brissot, Pierre, Ropert, Martine, Cavey, Thibault and Loréal, Olivier. (2019). Ceruloplasmin deficiency does not induce macrophagic iron overload: Lessons from a new rat model of hereditary aceruloplasminemia. The FASEB Journal. 33(12), pp. 13492 - 13502. https://doi.org/10.1096/fj.201901106R
Mitochondrial MDM2 regulates respiratory complex i activity independently of p53
Arena, Giuseppe, Cissé, Madi Yann, Pyrdziak, Samuel, Chatre, Laurent, Riscal, Romain, Fuentes, Maryse, Arnold, Jamie Jon, Kastner, Markus, Gayte, Laurie, Bertrand-Gaday, Christelle, Nay, Kevin, Angebault-Prouteau, Claire, Murray, Kerren, Chabi, Beatrice, Koechlin-Ramonatxo, Christelle, Orsetti, Béatrice, Vincent, Charles, Casas, François, Marine, Jean-Christophe, ... Le Cam, Laurent. (2018). Mitochondrial MDM2 regulates respiratory complex i activity independently of p53. Molecular Cell. 69(4), pp. 594 - 609. https://doi.org/10.1016/j.molcel.2018.01.023