Top

BMC Pulmonary Medicine

Published in:

Open Access 01-12-2020 | Research article

Pulmonary inflammation-induced alterations in key regulators of mitophagy and mitochondrial biogenesis in murine skeletal muscle

Authors: Pieter A. Leermakers, Alexander H. V. Remels, Ramon C. J. Langen, Annemie M. W. J. Schols, Harry R. Gosker

Published in: BMC Pulmonary Medicine | Issue 1/2020

Abstract

Background

Both mitophagy, a selective mechanism for clearance of mitochondria, and mitochondrial biogenesis are key processes determining mitochondrial content and oxidative capacity of the musculature. Abnormalities in these processes could therefore contribute to deterioration of peripheral muscle oxidative capacity as observed in e.g. chronic obstructive pulmonary disease. Although it has been suggested that inflammatory mediators can modulate both mitophagy and mitochondrial biogenesis, it is unknown whether acute pulmonary inflammation affects these processes in oxidative and glycolytic skeletal muscle in vivo. Therefore, we hypothesised that molecular signalling patterns of mitochondrial breakdown and biogenesis temporally shift towards increased breakdown and decreased biogenesis in the skeletal muscle of mice exposed to one single bolus of IT-LPS, as a model for acute lung injury and pulmonary inflammation.

Methods

We investigated multiple important constituents and molecular regulators of mitochondrial breakdown, biogenesis, dynamics, and mitochondrial content in skeletal muscle over time in a murine (FVB/N background) model of acute pulmonary- and systemic inflammation induced by a single bolus of intra-tracheally (IT)-instilled lipopolysaccharide (LPS). Moreover, we compared the expression of these constituents between gastrocnemius and soleus muscle.

Results

Both in soleus and gastrocnemius muscle, IT-LPS instillation resulted in molecular patterns indicative of activation of mitophagy. This coincided with modulation of mRNA transcript abundance of genes involved in mitochondrial fusion and fission as well as an initial decrease and subsequent recovery of transcript levels of key proteins involved in the molecular regulation of mitochondrial biogenesis. Moreover, no solid differences in markers for mitochondrial content were found.

Conclusions

These data suggest that one bolus of IT-LPS results in a temporal modulation of mitochondrial clearance and biogenesis in both oxidative and glycolytic skeletal muscle, which is insufficient to result in a reduction of mitochondrial content.

Maltais F, Decramer M, Casaburi R, Barreiro E, Burelle Y, Debigare R, Dekhuijzen PN, Franssen F, Gayan-Ramirez G, Gea J, et al. An official American Thoracic Society/European Respiratory Society statement: update on limb muscle dysfunction in chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2014;189(9):e15–62.PubMedPubMedCentralCrossRef

Sapey E, Stockley RA. COPD exacerbations . 2: aetiology. Thorax. 2006;61(3):250–8.PubMedPubMedCentralCrossRef

Perera WR, Hurst JR, Wilkinson TM, Sapsford RJ, Mullerova H, Donaldson GC, Wedzicha JA. Inflammatory changes, recovery and recurrence at COPD exacerbation. Eur Respir J. 2007;29(3):527–34.PubMedCrossRef

Crul T, Testelmans D, Spruit MA, Troosters T, Gosselink R, Geeraerts I, Decramer M, Gayan-Ramirez G. Gene expression profiling in vastus lateralis muscle during an acute exacerbation of COPD. Cell Physiol Biochem. 2010;25(4–5):491–500.PubMedCrossRef

Romanello V, Sandri M. Mitochondrial quality control and muscle mass maintenance. Front Physiol. 2015;6:422.PubMed

Gomes LC, Scorrano L. Mitochondrial morphology in mitophagy and macroautophagy. Biochim Biophys Acta. 2013;1833(1):205–12.PubMedCrossRef

Wei H, Liu L, Chen Q. Selective removal of mitochondria via mitophagy: distinct pathways for different mitochondrial stresses. Biochim Biophys Acta. 2015;1853(10 Pt B):2784–90.PubMedCrossRef

Eiyama A, Okamoto K. PINK1/Parkin-mediated mitophagy in mammalian cells. Curr Opin Cell Biol. 2015;33:95–101.CrossRefPubMed

Gegg ME, Cooper JM, Chau KY, Rojo M, Schapira AH, Taanman JW. Mitofusin 1 and mitofusin 2 are ubiquitinated in a PINK1/parkin-dependent manner upon induction of mitophagy. Hum Mol Genet. 2010;19(24):4861–70.PubMedPubMedCentralCrossRef

10.

Hanna RA, Quinsay MN, Orogo AM, Giang K, Rikka S, Gustafsson AB. Microtubule-associated protein 1 light chain 3 (LC3) interacts with Bnip3 protein to selectively remove endoplasmic reticulum and mitochondria via autophagy. J Biol Chem. 2012;287(23):19094–104.PubMedPubMedCentralCrossRef

11.

Lazarou M, Sliter DA, Kane LA, Sarraf SA, Wang C, Burman JL, Sideris DP, Fogel AI, Youle RJ. The ubiquitin kinase PINK1 recruits autophagy receptors to induce mitophagy. Nature. 2015;524(7565):309–14.PubMedPubMedCentralCrossRef

12.

Schwarten M, Mohrluder J, Ma P, Stoldt M, Thielmann Y, Stangler T, Hersch N, Hoffmann B, Merkel R, Willbold D. Nix directly binds to GABARAP: a possible crosstalk between apoptosis and autophagy. Autophagy. 2009;5(5):690–8.PubMedCrossRef

13.

Yamaguchi O, Murakawa T, Nishida K, Otsu K. Receptor-mediated mitophagy. J Mol Cell Cardiol. 2016;95:50–6.PubMedCrossRef

14.

Correia JC, Ferreira DM, Ruas JL. Intercellular: local and systemic actions of skeletal muscle PGC-1s. Trends Endocrinol Metab. 2015;26(6):305–14.PubMedCrossRef

15.

Callahan LA, Supinski GS. Sepsis induces diaphragm electron transport chain dysfunction and protein depletion. Am J Respir Crit Care Med. 2005;172(7):861–8.PubMedCrossRef

16.

Jamart C, Gomes AV, Dewey S, Deldicque L, Raymackers JM, Francaux M. Regulation of ubiquitin-proteasome and autophagy pathways after acute LPS and epoxomicin administration in mice. BMC Musculoskelet Disord. 2014;15:166.PubMedPubMedCentralCrossRef

17.

Mofarrahi M, Sigala I, Guo Y, Godin R, Davis EC, Petrof B, Sandri M, Burelle Y, Hussain SN. Autophagy and skeletal muscles in sepsis. PLoS One. 2012;7(10):e47265.PubMedPubMedCentralCrossRef

18.

Stana F, Vujovic M, Mayaki D, Leduc-Gaudet JP, Leblanc P, Huck L, Hussain SNA. Differential regulation of the autophagy and proteasome pathways in skeletal muscles in sepsis. Crit Care Med. 2017;45(9):e971–9.PubMedCrossRef

19.

Moarbes V, Mayaki D, Huck L, Leblanc P, Vassilakopoulos T, Petrof BJ, Hussain SNA. Differential regulation of myofibrillar proteins in skeletal muscles of septic mice. Physiol Rep. 2019;7(20):e14248.PubMedPubMedCentralCrossRef

20.

Peruchi BB, Petronilho F, Rojas HA, Constantino L, Mina F, Vuolo F, Cardoso MR, Goncalves CL, Rezin GT, Streck EL, et al. Skeletal muscle electron transport chain dysfunction after sepsis in rats. J Surg Res. 2011;167(2):e333–8.PubMedCrossRef

21.

Zolfaghari PS, Carre JE, Parker N, Curtin NA, Duchen MR, Singer M. Skeletal muscle dysfunction is associated with derangements in mitochondrial bioenergetics (but not UCP3) in a rodent model of sepsis. Am J Phys Endocrinol Metab. 2015;308(9):E713–25.CrossRef

22.

Hansen ME, Simmons KJ, Tippetts TS, Thatcher MO, Saito RR, Hubbard ST, Trumbull AM, Parker BA, Taylor OJ, Bikman BT. Lipopolysaccharide disrupts mitochondrial physiology in skeletal muscle via disparate effects on Sphingolipid metabolism. Shock. 2015;44(6):585–92.PubMedPubMedCentralCrossRef

23.

Fredriksson K, Hammarqvist F, Strigard K, Hultenby K, Ljungqvist O, Wernerman J, Rooyackers O. Derangements in mitochondrial metabolism in intercostal and leg muscle of critically ill patients with sepsis-induced multiple organ failure. Am J Phys Endocrinol Metab. 2006;291(5):E1044–50.CrossRef

24.

Fredriksson K, Tjader I, Keller P, Petrovic N, Ahlman B, Scheele C, Wernerman J, Timmons JA, Rooyackers O. Dysregulation of mitochondrial dynamics and the muscle transcriptome in ICU patients suffering from sepsis induced multiple organ failure. PLoS One. 2008;3(11):e3686.PubMedPubMedCentralCrossRef

25.

Kishta OA, Guo Y, Mofarrahi M, Stana F, Lands LC, Hussain SNA. Pulmonary Pseudomonas aeruginosa infection induces autophagy and proteasome proteolytic pathways in skeletal muscles: effects of a pressurized whey protein-based diet in mice. Food Nutr Res. 2017;61(1):1325309.PubMedPubMedCentralCrossRef

26.

Komatsu R, Okazaki T, Ebihara S, Kobayashi M, Tsukita Y, Nihei M, Sugiura H, Niu K, Ebihara T, Ichinose M. Aspiration pneumonia induces muscle atrophy in the respiratory, skeletal, and swallowing systems. J Cachexia Sarcopenia Muscle. 2018;9(4):643–53.PubMedPubMedCentralCrossRef

27.

Langen RC, Haegens A, Vernooy JH, Wouters EF, de Winther MP, Carlsen H, Steele C, Shoelson SE, Schols AM. NF-kappaB activation is required for the transition of pulmonary inflammation to muscle atrophy. Am J Respir Cell Mol Biol. 2012;47(3):288–97.PubMedPubMedCentralCrossRef

28.

Haegens A, Heeringa P, van Suylen RJ, Steele C, Aratani Y, O'Donoghue RJ, Mutsaers SE, Mossman BT, Wouters EF, Vernooy JH. Myeloperoxidase deficiency attenuates lipopolysaccharide-induced acute lung inflammation and subsequent cytokine and chemokine production. J Immunol. 2009;182(12):7990–6.PubMedCrossRef

29.

Gamble L, Bagby GJ, Quinton LJ, Happel KI, Mizgerd JP, Zhang P, Nelson S. The systemic and pulmonary LPS binding protein response to intratracheal lipopolysaccharide. Shock. 2009;31(2):212–7.PubMedCrossRef

30.

Vernooy JH, Dentener MA, van Suylen RJ, Buurman WA, Wouters EF. Intratracheal instillation of lipopolysaccharide in mice induces apoptosis in bronchial epithelial cells: no role for tumor necrosis factor-alpha and infiltrating neutrophils. Am J Respir Cell Mol Biol. 2001;24(5):569–76.PubMedCrossRef

31.

Grundy D. Principles and standards for reporting animal experiments in the journal of physiology and experimental physiology. J Physiol. 2015;593(12):2547–9.PubMedPubMedCentralCrossRef

32.

Tsirigotis M, Thurig S, Dube M, Vanderhyden BC, Zhang M, Gray DA. Analysis of ubiquitination in vivo using a transgenic mouse model. BioTechniques. 2001;31(1):120–6, 128, 130.PubMedCrossRef

33.

Ceelen JJM, Schols A, Thielen NGM, Haegens A, Gray DA, Kelders M, de Theije CC, Langen RCJ. Pulmonary inflammation-induced loss and subsequent recovery of skeletal muscle mass require functional poly-ubiquitin conjugation. Respir Res. 2018;19(1):80.PubMedPubMedCentralCrossRef

34.

Slot IG, Schols AM, de Theije CC, Snepvangers FJ, Gosker HR. Alterations in skeletal muscle oxidative phenotype in mice exposed to 3 weeks of normobaric hypoxia. J Cell Physiol. 2016;231(2):377–92.PubMedCrossRef

35.

Zhang J, Ney PA. Role of BNIP3 and NIX in cell death, autophagy, and mitophagy. Cell Death Differ. 2009;16(7):939–46.PubMedCrossRef

36.

Burton TR, Gibson SB. The role of Bcl-2 family member BNIP3 in cell death and disease: NIPping at the heels of cell death. Cell Death Differ. 2009;16(4):515–23.PubMedCrossRef

37.

Chen M, Chen Z, Wang Y, Tan Z, Zhu C, Li Y, Han Z, Chen L, Gao R, Liu L, et al. Mitophagy receptor FUNDC1 regulates mitochondrial dynamics and mitophagy. Autophagy. 2016;12(4):689–702.PubMedPubMedCentralCrossRef

38.

Wu W, Tian W, Hu Z, Chen G, Huang L, Li W, Zhang X, Xue P, Zhou C, Liu L, et al. ULK1 translocates to mitochondria and phosphorylates FUNDC1 to regulate mitophagy. EMBO Rep. 2014;15(5):566–75.PubMedPubMedCentralCrossRef

39.

Liu L, Feng D, Chen G, Chen M, Zheng Q, Song P, Ma Q, Zhu C, Wang R, Qi W, et al. Mitochondrial outer-membrane protein FUNDC1 mediates hypoxia-induced mitophagy in mammalian cells. Nat Cell Biol. 2012;14(2):177–85.CrossRefPubMed

40.

Lv M, Wang C, Li F, Peng J, Wen B, Gong Q, Shi Y, Tang Y. Structural insights into the recognition of phosphorylated FUNDC1 by LC3B in mitophagy. Protein Cell. 2017;8(1):25–38.PubMedCrossRef

41.

Chen Z, Liu L, Cheng Q, Li Y, Wu H, Zhang W, Wang Y, Sehgal SA, Siraj S, Wang X, et al. Mitochondrial E3 ligase MARCH5 regulates FUNDC1 to fine-tune hypoxic mitophagy. EMBO Rep. 2017;18(3):495–509.PubMedPubMedCentralCrossRef

42.

Chen Y, Dorn GW 2nd. PINK1-phosphorylated mitofusin 2 is a Parkin receptor for culling damaged mitochondria. Science. 2013;340(6131):471–5.PubMedPubMedCentralCrossRef

43.

Lin J, Handschin C, Spiegelman BM. Metabolic control through the PGC-1 family of transcription coactivators. Cell Metab. 2005;1(6):361–70.PubMedCrossRef

44.

Arany Z. PGC-1 coactivators and skeletal muscle adaptations in health and disease. Curr Opin Genet Dev. 2008;18(5):426–34.PubMedPubMedCentralCrossRef

45.

Dorn GW 2nd. Central Parkin: the evolving role of Parkin in the heart. Biochim Biophys Acta. 2016;1857(8):1307–12.PubMedPubMedCentralCrossRef

46.

Palikaras K, Tavernarakis N. Mitochondrial homeostasis: the interplay between mitophagy and mitochondrial biogenesis. Exp Gerontol. 2014;56:182–8.PubMedCrossRef

47.

Shin JH, Ko HS, Kang H, Lee Y, Lee YI, Pletinkova O, Troconso JC, Dawson VL, Dawson TM. PARIS (ZNF746) repression of PGC-1alpha contributes to neurodegeneration in Parkinson's disease. Cell. 2011;144(5):689–702.PubMedPubMedCentralCrossRef

48.

Sin J, Andres AM, Taylor DJ, Weston T, Hiraumi Y, Stotland A, Kim BJ, Huang C, Doran KS, Gottlieb RA. Mitophagy is required for mitochondrial biogenesis and myogenic differentiation of C2C12 myoblasts. Autophagy. 2016;12(2):369–80.PubMedCrossRef

49.

Poole AC, Thomas RE, Yu S, Vincow ES, Pallanck L. The mitochondrial fusion-promoting factor mitofusin is a substrate of the PINK1/parkin pathway. PLoS One. 2010;5(4):e10054.PubMedPubMedCentralCrossRef

50.

Pryde KR, Smith HL, Chau KY, Schapira AH. PINK1 disables the anti-fission machinery to segregate damaged mitochondria for mitophagy. J Cell Biol. 2016;213(2):163–71.PubMedPubMedCentralCrossRef

51.

Liesa M, Borda-d'Agua B, Medina-Gomez G, Lelliott CJ, Paz JC, Rojo M, Palacin M, Vidal-Puig A, Zorzano A. Mitochondrial fusion is increased by the nuclear coactivator PGC-1beta. PLoS One. 2008;3(10):e3613.PubMedPubMedCentralCrossRef

52.

Soriano FX, Liesa M, Bach D, Chan DC, Palacin M, Zorzano A. Evidence for a mitochondrial regulatory pathway defined by peroxisome proliferator-activated receptor-gamma coactivator-1 alpha, estrogen-related receptor-alpha, and mitofusin 2. Diabetes. 2006;55(6):1783–91.PubMedCrossRef

53.

Remels AH, Gosker HR, Bakker J, Guttridge DC, Schols AM, Langen RC. Regulation of skeletal muscle oxidative phenotype by classical NF-kappaB signalling. Biochim Biophys Acta. 2013;1832(8):1313–25.PubMedCrossRef

54.

Remels AH, Gosker HR, Langen RC, Polkey M, Sliwinski P, Galdiz J, van den Borst B, Pansters NA, Schols AM. Classical NF-kappaB activation impairs skeletal muscle oxidative phenotype by reducing IKK-alpha expression. Biochim Biophys Acta. 2014;1842(2):175–85.PubMedCrossRef

55.

Mofarrahi M, Guo Y, Haspel JA, Choi AM, Davis EC, Gouspillou G, Hepple RT, Godin R, Burelle Y, Hussain SN. Autophagic flux and oxidative capacity of skeletal muscles during acute starvation. Autophagy. 2013;9(10):1604–20.PubMedCrossRef

56.

Leermakers PA, Kneppers AEM, Schols A, Kelders M, de Theije CC, Verdijk LB, van Loon LJC, Langen RCJ, Gosker HR. Skeletal muscle unloading results in increased mitophagy and decreased mitochondrial biogenesis regulation. Muscle Nerve. 2019;60(6):769–78.PubMedPubMedCentralCrossRef

Title: Pulmonary inflammation-induced alterations in key regulators of mitophagy and mitochondrial biogenesis in murine skeletal muscle
Authors: Pieter A. Leermakers
Alexander H. V. Remels
Ramon C. J. Langen
Annemie M. W. J. Schols
Harry R. Gosker
Publication date: 01-12-2020
Publisher: BioMed Central
Published in: BMC Pulmonary Medicine / Issue 1/2020
Electronic ISSN: 1471-2466
DOI: https://doi.org/10.1186/s12890-020-1047-8

ACC 2024 Congress Coverage

Heart Failure Video

Keynote webinar | Spotlight on sleep in brain health

Springer Medicine

Pulmonary inflammation-induced alterations in key regulators of mitophagy and mitochondrial biogenesis in murine skeletal muscle

Abstract

Background

Methods

Results

Conclusions

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

Incentivised to exercise

New intervention for STEMI-related cardiogenic shock

» View more highlights on the ACC 2024 congress hub page

Keynote webinar | Spotlight on sleep in brain health

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

Please log in to get access to this content

Other articles of this Issue 1/2020

Prognostic value of pretreatment platelet counts in lung cancer: a systematic review and meta-analysis

Digital versus analogue chest drainage system in patients with primary spontaneous pneumothorax: a randomized controlled trial

Comorbidities associated with nontuberculous mycobacterial disease in Japanese adults: a claims-data analysis

Impact of radiological honeycombing in rheumatoid arthritis-associated interstitial lung disease

New-onset nontuberculous mycobacterial pulmonary disease in bronchiectasis: tracking the clinical and radiographic changes

Pulmonary cryptococcosis coexisting with central type lung cancer in an immuocompetent patient: a case report and literature review

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

Incentivised to exercise

New intervention for STEMI-related cardiogenic shock

» View more highlights on the ACC 2024 congress hub page