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I Sarcolipin Overexpression Improves Fatigue Resistance by Enhancing Sarcolipin Overexpression Improves Fatigue Resistance by Enhancing Skeletal Muscle Energetics DISSERTATION Presented in Partial Fulfillment of the Requirements for the Degree Doctor of Philosophy in the Graduate School of The Ohio State University By Danesh Hooshmand Sopariwala Ohio State Biochemistry Program The Ohio State University 2015 Dissertation Committee: Muthu Periasamy, PhD, Advisor Jill Rafael-Fortney, PhD Jianjie Ma, PhD Paul Janssen, PhD Noah Weisleder, PhD i Copyright by Danesh Hooshmand Sopariwala 2015 ii Abstract Sarcolipin (SLN) is a regulator of sarco(endo)plasmic reticulum calcium ATPase (SERCA) in skeletal muscle. Recent studies using SLN knockout (Sln-/-) mice have identified SLN as a key player in muscle thermogenesis and metabolism. In this study, we exploited a SLN overexpression (SlnOE) mouse model to determine how increased SLN level affected, metabolic rate, exercise capacity/ fatigue in whole animals and isolated muscle, as well as muscle contractile properties and calcium dynamics. We found that SlnOE mice were more resistant to fatigue and ran significantly longer distance than wild type (WT). Studies with isolated extensor digitorum longus (EDL) muscle showed that SlnOE EDL produced higher twitch force than WT. The force-frequency curves were not different between WT and SlnOE EDLs, but at lower frequencies the pyruvate induced potentiation of force had greater significance in SlnOE EDL than WT. SLN overexpression did not alter the twitch and force frequency curve in isolated soleus muscle. However, during a 10 minute fatigue protocol both EDL and soleus from SlnOE mice fatigued significantly less than WT muscles. Although the expression of mitochondrial oxidative phosphorylation enzymes and isolated mitochondrial respiration was not different between WT and SlnOE muscles, the latter showed higher carnitine palmitoyl transferase-1 protein expression, which could enhance fatty acid metabolism. In addition, lactate dehydrogenase expression was higher in SlnOE ii EDL suggesting increased glycolytic capacity. SLN overexpression resulted in altered myplasmic Ca2+ dynamics as measured in isolated flexor digitorum brevis (FDB) fibers. FDB fibers from SlnOE mice had a significantly longer decay phase of Ca2+ transient during a single twitch and also showed a significant increase in store operated calcium entry (SOCE) and basal Ca2+, than WT FDB fibers. Moreover, the levels of key SOCE proteins like stromal interaction molecule 1, transient receptor like ion channel C 3 (TRPC 3) and TRPC 4 were significantly higher in SlnOE FDB fibers than WT. In addition, we showed that inhibition of SOCE caused a greater reduction in force of SlnOE EDL than WT EDL during fatigue. Furthermore, the increased muscle energetics and improved resistance to fatigue of SlnOE mice enabled them to rescue Sln-/- mice from acute cold induced hypothermia. These data allow us to conclude that increased SLN expression improves skeletal muscle and whole animal performance during prolonged physical activity. iii Dedication To my parents, especially my mother, the most courageous person I know. iv Acknowledgments My doctoral research experience has been a journey of personal and scientific discovery unlike any other. I hope this work advances the wonderful field of muscle physiology and metabolism even if it is in the slightest, and for this I have a number of people to thank. First and foremost is my mentor Dr. Muthu Periasamy, who has been very patient and understanding and given me the space to do my research while at the same time making sure that I was not deviating from my goal. The intellectually stimulating weekly meetings and the training I have received have given me the tools to confidently embark on my post-doctoral and future research career. I have also had immense help from my committee members, Dr. Jill Rafael-Fortney, Dr. Jianjie Ma, Dr. Paul Janssen and Dr. Noah Weisleder. Their valuable insight and excellent suggestions have played a profound role in shaping my project. During the course of my research I have had the good fortune of collaborating with and learning from researchers who are leaders in their respective fields. I am grateful to Dr. Ma, Dr. Weisleder, Dr. Zui Pan and Dr. Ki Ho Park for their help with the store operated calcium entry studies and for giving me the opportunity to learn a new technique. I am very thankful to Dr. Jeffery Molkentin at University of Cincinnati and Dr. Sanjeeva Goonasekera for collaborating on generating the Sarcolipin overexpression mouse model. I am grateful to Dr. Douglas Pfeiffer and Dr. Adam Rauckhorst for their v help with the isolated mitochondrial oxygen measurements. I am also much obliged to Dr. Robert Dirksen at University of Rochester for hosting my visit to his laboratory. Moreover, I want to express my gratitude to Dr. Lan Wei-Lapierre from Dr. Dirksen’s lab for performing the calcium transient studies. It would have been almost impossible to accomplish whatever little I have, without the wonderful work environment in the Periasamy lab. Nobody understands the love hate relationship I have with Sarcolipin, better than my colleagues. I am thankful to all Periasamy lab members, present and prior, for their experimental and literary inputs. I especially want to thank Dr. Santosh K. Maurya for allowing me to present some of his work, Meghna Pant for performing the RNA quantification and Leslie Rowland for helping me with the isolated mitochondrial studies. Last but not least I thank my family members who have been by my side via Skype through all the ups and downs. Finally, words cannot express how much I appreciate my beautiful wife Sana A. Shaikh for supporting me professionally and personally at every step of the way. vi Vita 2005 ............................................................ B.S. Chemistry, Fergusson College (Pune, India) 2007 ............................................................ M.S. Biochemistry, University of Pune (Pune, India) 2008 to present ........................................... Graduate Research Associate, Department of Physiology and Cell Biology, The Ohio State University Publications Sahoo SK*, Shaikh SA*, Sopariwala DH, Bal NC, Bruhn DS, Kopec W, Khandelia H and Periasamy M, (2015), ‘The N-Terminus of Sarcolipin plays an important role in uncoupling Sarco-endoplasmic Reticulum Ca2+ ATPase (SERCA) ATP hydrolysis from Ca2+ transport’, J. Biol. Chem, (In press) April 16 doi:10.1074/jbc.M115.636738. Pant M*, Sopariwala DH*, Bal NC, Lowe J, Delfín DA, Rafael-Fortney J and Periasamy M, (2015), ‘Metabolic dysfunction and altered mitochondrial dynamics in the utrophin- dystrophin deficient mouse model of Duchenne muscular dystrophy’, PLOS One Apr 10;10(4):e0123875. doi: 10.1371/journal.pone.0123875 vii Maurya SK, Bal NC, Sopariwala DH, Pant M, Rowland LA, Shaikh SA, and Periasamy M, (2015), ‘Sarcolipin is a key determinant of basal metabolic rate and its overexpression enhances energy expenditure and resist against diet induced obesity’, J. Biol. Chem (Accepted Feb 24th 2015 – In press) doi: 10.1074/jbc.M115.636878 Sopariwala DH, Pant M, Shaikh SA, Goonasekera SA, Molkentin JD, Weisleder N, Ma J, Pan Z and Periasamy M, (2015), ‘Sarcolipin overexpression improves muscle energetics and reduces fatigue’, J. Appl. Physiol. (Accepted Feb 20th 2015– In press) doi: 10.1152/japplphysiol.01066.2014 Pant M, Sopariwala DH and Bal NC, (2014), ‘Malignant hyperthermia: to buffer or not to buffer’, J. Physiol., Mar 1;592 (Pt 5):827-8. doi: 10.1113/jphysiol.2013.267906. Sahoo SK, Shaikh SA, Sopariwala DH, Bal NC, Periasamy M, (2013), ‘Sarcolipin protein interaction with sarco(endo)plasmic reticulum Ca2+ ATPase (SERCA) is distinct from phospholamban protein, and only sarcolipin can promote uncoupling of the SERCA pump’, J. Biol. Chem. Mar 8;288(10):6881-9. doi: 10.1074/jbc.M112.436915. Bal NC, Maurya SK#, Sopariwala DH#, Sahoo SK, Gupta SC, Shaikh SA, Pant M, Rowland LA, Bombardier E, Goonasekera SA, Tupling AR, Molkentin JD, Periasamy M, (2012), ‘Sarcolipin is a newly identified regulator of muscle-based thermogenesis in mammals’, Nat. Med. Oct;18(10):1575-9. doi:10.1038/nm.2897. viii Chi M, Zhou Y, Sopariwala DH, Periasamy M, (2011), ‘SM2+/- male mice are predisposed to develop urinary tract obstruction and hyper contractility of the bladder smooth muscle upon ageing’ J Smooth Muscle Res.; 47 (3-4):67-78. doi: 10.1540/jsmr.47.67. Bal NC, Jena N, Sopariwala DH, Balaraju T, Shaikh S, Bal C, Sharon A, Gyorke S and Periasamy M, (2011), ‘Probing cationic selectivity of Cardiac Calsequestrin and its CPVT mutants’ Biochem J. 435(2): 391-399. doi:10.1042/BJ20101771. * Indicates co-first authorship. # Indicates co-second authorship. Fields of Study Major Field: Ohio State Biochemistry Program ix Table of Contents Abstract .......................................................................................................................... ii Dedication ..................................................................................................................... iv Acknowledgments ...........................................................................................................v Vita .............................................................................................................................. vii Fields of Study .............................................................................................................. ix List of Tables................................................................................................................xiv
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