FROM OUR LAB’S PROJECTS

LIM and Cysteine-rich Domains 1 (LMCD1) regulates skeletal muscle hypertrophy, calcium handling, and force.
Ferreira DMS, Cheng AJ, Agudelo LZ, Cervenka I, Chaillou T, Correia JC, Porsmyr-Palmertz M, Izadi M, Hansson A, Martínez-Redondo V, Valente-Silva P, Pettersson-Klein AT, Estall JL, Robinson MM, Nair KS, Lanner JT, Ruas JL. 
Skelet. Muscle. 2019 Oct 31;9(1):26.

One of the goals of our lab is to identify molecules that are important for maintaining muscle mass and strength. In this paper we identify LMCD1 as an important regulator of muscle size that also increases contraction power.

Skeletal muscle PGC-1α1 reroutes kynurenine metabolism to increase energy efficiency and fatigue-resistance.
Agudelo LZ, Ferreira DMS, Dadvar S, Cervenka I, Ketscher L, Izadi M, Zhengye L, Furrer R, Handschin C, Venckunas T, Brazaitis M, Kamandulis S, Lanner JT, Ruas JL.
Nat Commun. 2019 Jun 24;10(1):2767.

In this paper we describe a new mechanism that allows muscle to become more energy efficient as you perform endurance training. We also found that when this mechanism is active, your muscles can use a neurotoxic molecule (kynurenine) to support energy production.

Small molecule PGC-1α1 protein stabilizers induce adipocyte Ucp1 expression and uncoupled mitochondrial respiration.
Pettersson-Klein AT, Izadi M, Ferreira DMS, Cervenka I, Correia JC, Martinez-Redondo V, Southern M, Cameron M, Kamenecka T, Agudelo LZ, Porsmyr-Palmertz M, Martens U, Lundgren B, Otrocka M, Jenmalm-Jensen A, Griffin PR, Ruas JL.
Mol Metab. 2018 Mar;9:28-42.

PGC-1α molecules are important for our muscles to respond and adapt to exercise training programs. Mouse studies have indicated that finding ways to keep high PGC-1α levels in muscle, fat, or brain could be beneficial for many diseases. Here we report the discovery of several chemical compounds that increase PGC-1α levels in fat cell cultures in the lab, and increase their energy expenditure. They could be further developed to be active in live animals and in different tissues.

Kynurenic Acid and Gpr35 Regulate Adipose Tissue Energy Homeostasis and Inflammation.
Agudelo LZ, Ferreira DMS, Cervenka I, Bryzgalova G, Dadvar S, Jannig PR, Pettersson-Klein AT, Lakshmikanth T, Sustarsic EG, Porsmyr-Palmertz M, Correia JC, Izadi M, Martínez-Redondo V, Ueland PM, Midttun Ø, Gerhart-Hines Z, Brodin P, Pereira T, Berggren PO, Ruas JL.
Cell Metab. 2018 Feb 6;27(2):378-392.e5.

Exercise training is well known for increasing the energy our muscles use, reducing how much our adipose tissues stores, but also for changing our immune system. In this paper we found that during exercise, muscle secretes into circulation a small molecule (kynurenic acid) that activates a cell surface receptor (GPR35) in both fat cells and certain immune cells that reside in the adipose tissue. The result of this inter-organ communication is higher energy expenditure, and an anti-inflammatory state of the adipose tissue.

Neurturin is a PGC-1α1-controlled myokine that promotes motor neuron recruitment and neuromuscular junction formation.
Mills R, Taylor-Weiner H, Correia JC, Agudelo LZ, Allodi I, Kolonelou C, Martinez-Redondo V, Ferreira DMS, Nichterwitz S, Comley LH, Lundin V, Hedlund E, Ruas JL, Teixeira AI.
Mol Metab. 2018 Jan;7:12-22.

This study was developed in close collaboration with the laboratory of Dr. Ana Teixeira(MBB, KI). We wanted to understand how changes that occur inside the muscle fibers (when we exercise or in situations of muscle disease) are communicated to the neurons that bring information from the brain and that allow us to move (motor neurons). We identified a molecule called Neurturin, that is released from muscle and encourages motor neurons to stay connected to muscle. This finding could have implications in diseases such as ALS.

Peroxisome Proliferator-activated Receptor γ Coactivator-1 α Isoforms Selectively Regulate Multiple Splicing Events on Target Genes.
Martínez-Redondo V, Jannig PR, Correia JC, Ferreira DM, Cervenka I, Lindvall JM, Sinha I, Izadi M, Pettersson-Klein AT, Agudelo LZ, Gimenez-Cassina A, Brum PC, Dahlman-Wright K, Ruas JL.
J Biol Chem. 2016 Jul 15;291(29):15169-84.

PGC-1α proteins can change cellular functions by changing the expression (transcription) of different genes. There are several PGC-1α proteins, which affect different sets of genes. Here we found that the different PGC-1α proteins can also change how genes are read (transcribed) so the same genetic information can give rise to different cellular messengers (mRNAs) and effectors (proteins). This process is called alternative splicing.

Bioenergetic cues shift FXR splicing towards FXRα2 to modulate hepatic lipolysis and fatty acid metabolism.
Correia JC, Massart J, de Boer JF, Porsmyr-Palmertz M, Martínez-Redondo V, Agudelo LZ, Sinha I, Meierhofer D, Ribeiro V, Björnholm M, Sauer S, Dahlman-Wright K, Zierath JR, Groen AK, Ruas JL.
Mol Metab. 2015 Sep 26;4(12):891-902.

Alternative splicing is a common process by which the same genetic information can be read (transcribed) in different ways, and produce different proteins, with potentially different activities. The bile acid receptor FXR is no exception, although it wasn’t known why cells are able to produce 4 different receptors from the same gene. We found that alternative splicing of the FXR gene can result in changes in liver metabolism that protect from hepatic fat accumulation.

Skeletal muscle PGC-1α1 modulates kynurenine metabolism and mediates resilience to stress-induced depression.
Agudelo LZ, Femenía T, Orhan F, Porsmyr-Palmertz M, Goiny M, Martinez-Redondo V, Correia JC, Izadi M, Bhat M, Schuppe-Koistinen I, Pettersson AT, Ferreira DMS, Krook A, Barres R, Zierath JR, Erhardt S, Lindskog M, Ruas JL.
Cell. 2014 Sep 25;159(1):33-45.

Exercise can prevent or treat mild to moderate cases of stress-induced depression, although the mechanisms weren’t known. We found one mechanism that protects the brain from changes elicited by unpredictable stress, which are associated with the development of depression. In brief, if you train your muscles (through aerobic exercise), they acquire the capacity to filter out of the blood a molecule called kynurenine. Kynurenine is known to increase in circulation under stress and to accumulate in the brain, where it correlates with the development of depression.

You can find additional comments to this paper in:
“Muscle over Mind”. Cell Metab. 2014.
“Muscling in on Depression”. N. Engl. J. Med. 2014. Clinical Implications of Basic Research.

A PGC-1α isoform induced by resistance training regulates skeletal muscle hypertrophy.
Ruas JL, White JP, Rao RR, Kleiner S, Brannan KT, Harrison BC, Greene NP, Wu J, Estall JL, Irving BA, Lanza IR, Rasbach KA, Okutsu M, Nair KS, Yan Z, Leinwand LA, Spiegelman BM.
Cell. 2012 Dec 7;151(6):1319-31.

How do our muscle grow bigger when we perform resistance exercise (for example, lifting weights)? Why don’t they grow as big if we instead perform endurance exercise (like running)? In this study we found that depending on what kind of exercise you perform, muscle cells read (transcribe) the PGC-1α gene in a different way (alternative splicing again!). Endurance training produces a PGC-1α protein variant that makes muscle more energy efficient, whereas resistance training favours another variant linked to muscle growth and strength. Finding ways to selectively increase these PGC-1α variants could help patients with, for example, muscle weakness.

You can finds additional comments to this paper in:
“Making muscle of mitochondria by selective splicing of PGC-1α”. Cell Metab. 2013.


  FROM COLLABORATION PROJECTS 


PGC-1α isoforms coordinate to balance hepatic metabolism and apoptosis in inflammatory environments.
Léveillé M, Besse-Patin A, Jouvet N, Gunes A, Jeromson S, Khan NP, Sczelecki S, Baldwin C, Dumouchel A, Correia J, Jannig P, Boulais J,
Ruas JL, Estall JL. 
Mol. Metab. 2020 Jan 11; 34:72-84. 

 

Modeling the transport of nuclear proteins along single skeletal muscle cells.
Taylor-Weiner H, Grigsby CL, Ferreira DMS, Dias JM, Stevens MM, Ruas JL, Teixeira AI. 
Natl. Acad. Sci. U.S.A. 2020 Feb 11;117(6):2978-2986. 

 

Dietary attenuates high-fat diet-induced obesity via mechanisms involving higher adipocyte respiration and alterations in inflammatory status.
Peleli M, Ferreira DMS, Tarnawski L, McCann S, Li X, Zhuge Z, Newton P, Massart J, Chagin A, Olofsson P, Ruas JL, Weitzberg E, Lundberg J, and Carlstrom M. 
Redox Biol. 2020 Jan;28:101387. 

 

Transcriptomic analysis of the development of skeletal muscle atrophy in cancer-cachexia in tumor-bearing mice.
Blackwell TA, Cervenka I, Khatri B, Brown JL, Rosa-Caldwell ME, Lee DE, Perry RA Jr, Brown LA, Haynie WS, Wiggs MP, Bottje WG, Washington TA, Kong BC, Ruas JL, Greene NP.
Physiol Genomics. 2018 Dec 1;50(12):1071-1082.

Cited4 is a sex-biased mediator of the antidiabetic glitazone response in adipocyte progenitors..
Bayindir-Buchhalter I, Wolff G, Lerch S, Sijmonsma T, Schuster M, Gronych J, Billeter AT, Babaei R, Krunic D, Ketscher L, Spielmann N, Hrabe de Angelis M, Ruas JL, Müller-Stich BP, Heikenwalder M, Lichter P, Herzig S, Vegiopoulos A.
EMBO Mol Med. 2018 Aug;10(8). pii: e8613.

Human Carboxylesterase 2 Reverses Obesity-Induced Diacylglycerol Accumulation and Glucose Intolerance.
Ruby MA, Massart J, Hunerdosse DM, Schönke M, Correia JC, Louie SM, Ruas JL, Näslund E, Nomura DK, Zierath JR.
Cell Rep. 2017 Jan 17;18(3):636-646.

Endurance exercise increases skeletal muscle kynurenine aminotransferases and plasma kynurenic acid in humans.
Schlittler M, Goiny M, Agudelo LZ, Venckunas T, Brazaitis M, Skurvydas A, Kamandulis S, Ruas JL, Erhardt S, Westerblad H, Andersson DC.
Am J Physiol Cell Physiol. 2016 May 15;310(10):C836-40.

Mechano-signalling pathways in an experimental intensive critical illness myopathy model.
Corpeno Kalamgi R, Salah H, Gastaldello S, Martinez-Redondo V, Ruas JL, Fury W, Bai Y, Gromada J, Sartori R, Guttridge DC, Sandri M, Larsson L.
J Physiol. 2016 Aug 1;594(15):4371-88.

Ryanodine receptor fragmentation and sarcoplasmic reticulum Ca2+ leak after one session of high-intensity interval exercise.
Place N, Ivarsson N, Venckunas T, Neyroud D, Brazaitis M, Cheng AJ, Ochala J, Kamandulis S, Girard S, Volungevičius G, Paužas H, Mekideche A, Kayser B, Martinez-Redondo V, Ruas JL, Bruton J, Truffert A, Lanner JT, Skurvydas A, Westerblad H.
Proc Natl Acad Sci U S A. 2015 Dec 15;112(50):15492-7.

G protein-coupled receptor 56 regulates mechanical overload-induced muscle hypertrophy.
White JP, Wrann CD, Rao RR, Nair SK, Jedrychowski MP, You JS, Martínez-Redondo V, Gygi SP, Ruas JL, Hornberger TA, Wu Z, Glass DJ, Piao X, Spiegelman BM.
Proc Natl Acad Sci U S A. 2014 Nov 4;111(44):15756-61.

Meteorin-like is a hormone that regulates immune-adipose interactions to increase beige fat thermogenesis.
Rao RR, Long JZ, White JP, Svensson KJ, Lou J, Lokurkar I, Jedrychowski MP, Ruas JL, Wrann CD, Lo JC, Camera DM, Lachey J, Gygi S, Seehra J, Hawley JA, Spiegelman BM.
Cell. 2014 Jun 5;157(6):1279-91.

Loss of Pgc-1α expression in aging mouse muscle potentiates glucose intolerance and systemic inflammation.
Sczelecki S, Besse-Patin A, Abboud A, Kleiner S, Laznik-Bogoslavski D, Wrann CD, Ruas JL, Haibe-Kains B, Estall JL.
Am J Physiol Endocrinol Metab. 2014 Jan 15;306(2):E157-67.


  REVIEWS & PERSPECTIVES


Exercised cytokines promote endurance.
Correia JC and Ruas JL.
Science 2020 May 1;368(6490):470-471.

Full text                  PDF

This is a perspective about the article by Knudsen et al., (Science 2020 May 1; 368(6490):eaat3987) where they show that exercise leads to the increase of ILC2 cells in muscle, and to higher levels of the cytokine IL13, which promotes endurance. Our text summarizes their findings in the context of what is currently known about how muscle adapts to exercise.

The Kynurenine connection: how exercise shifts muscle tryptophan metabolism and affects energy homeostasis, the immune system, and the brain.
Martin K, Azzolini M, and Ruas JL.
Am. J. Physiol. Cell Physiol. 2020. 318: C818–C830.

In this article we review the current understanding of how exercise and trained muscles can change the levels of compounds that result from the degradation of the amino acid tryptophan (they’re called kynurenines or kynurenine metabolites). There are several of these molecules and they can have diverse effects on the body. We also speculate on what directions this field might take in the future.

The weight of nutrients: kynurenine metabolites in obesity and exercise.
Dadvar S, Ferreira DMS, Cervenka I, Ruas JL.
J Intern Med. 2018 Nov;284(5):519-533.

This is a review article that summarizes current knowledge on how some nutrients obtained from food play a dual role in human health: they provide energy and building blocks for cells and tissues, but they also constitute important messengers that can impact mental health or how an organism decides to store energy or use it.

Kynurenines: Tryptophan’s metabolites in exercise, inflammation, and mental health.
Cervenka I, Agudelo LZ, Ruas JL.
Science. 2017 Jul 28;357(6349).

The amino acid tryptophan, which we get from food since our bodies cannot make it, has many different roles in the human body. We need it to make new proteins, but it is mostly used to generate many other molecules with different biological activities. From serotonin – that regulates mood, to melatonin – that regulates sleep, to a group of compounds called kynurenines that regulate many different processes in the body. This review summarizes what we known about the many roles of kynurenines.