Giovanni Baranello, M.D., Ph.D. ‡ Fondazione IRCCS Istituto Neurologico Carlo Besta Milan, Italy and UCL Great Ormond Street Institute of Child Health London, United Kingdom ORCID IDs: 0000-0002-1408-6971 (A.L.M.); 0000-0002-2950-0231 (A.A.); 0000-0003-4871-6692 (G.B.). *Corresponding author (e-mail: antonella.lomauro@polimi.it). ‡ These authors contributed equally to this work. References 1. Finkel RS, Chiriboga CA, Vajsar J, Day JW, Montes J, De Vivo DC, et al. Treatment of infantile-onset spinal muscular atrophy with nusinersen: a phase 2, open-label, dose-escalation study. Lancet 2016;388: 3017–3026. 2. Finkel RS, Mercuri E, Darras BT, Connolly AM, Kuntz NL, Kirschner J, et al.; ENDEAR Study Group. Nusinersen versus sham control in infantile-onset spinal muscular atrophy. N Engl J Med 2017;377: 1723–1732. 3. LoMauro A, Aliverti A, Mastella C, Arnoldi MT, Banfi P, Baranello G. Spontaneous breathing pattern as respiratory functional outcome in children with spinal muscular atrophy (SMA). PLoS One 2016;11: e0165818. 4. Kolb SJ, Coffey CS, Yankey JW, Krosschell K, Arnold WD, Rutkove SB, et al.; NeuroNEXT Clinical Trial Network on behalf of the NN101 SMA Biomarker Investigators. Natural history of infantile-onset spinal muscular atrophy. Ann Neurol 2017;82:883–891. 5. Finkel RS, McDermott MP, Kaufmann P, Darras BT, Chung WK, Sproule DM, et al. Observational study of spinal muscular atrophy type I and implications for clinical trials. Neurology 2014;83: 810–817. 6. Nicot F, Hart N, Forin V, Boul ´ e M, Cl ´ ement A, Polkey MI, et al. Respiratory muscle testing: a valuable tool for children with neuromuscular disorders. Am J Respir Crit Care Med 2006;174: 67–74. 7. LoMauro A, Banfi P, Mastella C, Alberti K, Baranello G, Aliverti A. A new method for measuring bell-shaped chest induced by impaired ribcage muscles in spinal muscular atrophy children. Front Neurol 2018;9:703. 8. Finkel R, Bertini E, Muntoni F, Mercuri E; ENMC SMA Workshop Study Group. 209th ENMC International Workshop: outcome measures and clinical trial readiness in spinal muscular atrophy 7-9 November 2014, Heemskerk, The Netherlands. Neuromuscul Disord 2015;25:593–602. 9. Glanzman AM, Mazzone E, Main M, Pelliccioni M, Wood J, Swoboda KJ, et al. The Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND): test development and reliability. Neuromuscul Disord 2010;20:155–161. 10. Glanzman AM, McDermott MP, Montes J, Martens WB, Flickinger J, Riley S, et al.; Pediatric Neuromuscular Clinical Research Network for Spinal Muscular Atrophy (PNCR); Muscle Study Group (MSG). Validation of the Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND). Pediatr Phys Ther 2011; 23:322–326. 11. Pane M, Coratti G, Sansone VA, Messina S, Bruno C, Catteruccia M, et al.; Italian Expanded Access Program Working Group. Nusinersen in type 1 spinal muscular atrophy: twelve-month real-world data. Ann Neurol 2019;86:443–451. 12. Aragon-Gawinska K, Seferian AM, Daron A, Gargaun E, Vuillerot C, Cances C, et al. Nusinersen in patients older than 7 months with spinal muscular atrophy type 1: a cohort study. Neurology 2018;91: e1312–e1318. 13. Finkel RS, Mercuri E, Meyer OH, Simonds AK, Schroth MK, Graham RJ, et al.; SMA Care group. Diagnosis and management of spinal muscular atrophy: Part 2: pulmonary and acute care; medications, supplements and immunizations; other organ systems; and ethics. Neuromuscul Disord 2018;28:197–207. 14. LoMauro A, Masson R, Mastella C, Aliverti A, Baranello G. The beneficial effect of nusinersen on the breathing pattern of SMA type 1 children. Presented at the 24th International Annual Congress of the World Muscle Society. October 1–5, 2019, Copenhagen, Denmark. Copyright © 2019 by the American Thoracic Society Is PKM2 Phosphorylation a Prerequisite for Oligomer Disassembly in Pulmonary Arterial Hypertension? To the Editor: Pulmonary arterial hypertension (PAH) is an incurable vascular disease characterized by pulmonary vascular remodeling and increased pulmonary vascular resistance, culminating in right ventricular failure (1). PAH shares major pathophysiological mechanisms with cancer, including substantial metabolic reprogramming with a shift toward glycolysis over mitochondrial oxidative phosphorylation (the Warburg effect). The final step in glycolysis is catalyzed by the enzyme pyruvate kinase (PK). The PK muscle gene (PKM) is alternatively spliced to produce PKM1, which forms constitutively active tetramers in terminally differentiated tissues, and PKM2, which forms both high-activity tetramers and low-activity dimers/monomers in proliferating cells and tumors (2). Conformational changes of PKM2 that affect the dynamic equilibrium of monomers, dimers, and tetramers are tightly controlled by numerous allosteric effectors (e.g., fructose-1,6-bisphosphate) and posttranslational modifications (e.g., phosphorylation at Y105 and S37). A shift in the PKM2 equilibrium from tetramers to low-activity dimers/monomers ultimately diverts the glycolytic flux into biosynthetic routes and promotes the Warburg effect. Thus, PKM2 oligomerization is a decision point that determines the ultimate activity of the enzyme, paving the way to metabolic reprogramming. Growth factor–stimulated ERK1/2-dependent phosphorylation leads to PKM2 nuclear translocation empowering the transcriptional activation of genes involved in metabolism (3). Furthermore, nuclear PKM2 acts as a coactivator of b-catenin to induce Cyclin D1 and c-Myc expression, highlighting the nonmetabolic role of PKM2 in cell-cycle progression (4). PKM2 nuclear function is regulated by the PARP-1 (poly-ADP ribose polymerase-1) signaling pathway, which has been established to play a crucial role in PAH development (5, 6). Elevated plasma dimeric PKM2 levels have been detected in various cancer types (2), identifying PKM2 as a potential Supported by funding from the Universities of Giessen and Marburg Lung Center, Excellence Cluster Cardiopulmonary System, and the German Research Foundation through Collaborative Research Center 1213, projects B4 and A8. H.G. and H.A.G. had full access to all the data in the study and take responsibility for its integrity and the data analysis. Originally Published in Press as DOI: 10.1164/rccm.201904-0782LE on September 5, 2019 CORRESPONDENCE 1550 American Journal of Respiratory and Critical Care Medicine Volume 200 Number 12 | December 15 2019