West Virginia University B.S. 08/ /2007 Exercise Physiology West Virginia University Colorado State University University of Virginia

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1 APPLICANT BIOGRAPHICAL SKETCH NAME OF APPLICANT: Joshua C Drake era COMMONS USER NAME (credential, e.g., agency login): J_DRAKE POSITION TITLE: Postdoctoral Fellow EDUCATION/TRAINING INSTITUTION AND LOCATION DEGREE (if applicable) START DATE MM/YYYY END DATE MM/YYYY FIELD OF STUDY West Virginia B.S. 08/ /2007 Exercise Physiology West Virginia Colorado State of Virginia M.S. Ph.D. Postdoc 08/ / / / /2014 Present Exercise Physiology Human Bioenergetics Molecular Physiology A. Personal Statement My long-term research interests are to development a comprehensive understanding of the key signaling mechanisms mediating how exercise promotes mitochondrial protein homeostasis (i.e. proteostasis) in skeletal muscle and how their alteration with age affects chronic disease susceptibility, metabolic health, exercise adaptation, and potential for healthy aging. My academic training and research experience have provided me with an excellent background in molecular exercise physiology, bioenergetics, gerontology, and comparative physiology. As a Master s student with Dr. David Williamson, my research focused on the dysregulation of mrna translation in skeletal muscle of ob/ob mice, where I gained expertise in the biochemical characterization of mrna translation complexes. Using two pharmacological means, I showed that activation of the energetic sensing kinase AMPK could normalize mrna translation in obese skeletal muscle, which led to two, firstauthored publications and a co-authored review. As a Ph.D. student with Drs. Karyn Hamilton and Benjamin Miller, my research focused on common mechanisms of slowed aging in several growth restricted mouse models of long life. I helped develop a novel method for measuring sub-cellular proteostasis (including mitochondria) across multiple tissues using stable isotope tracer technology to simultaneously measure long-term protein and DNA synthesis rates in vivo. I thus described a potential unifying mechanism of slowed aging across four independent mouse models of long life: life-long calorically restricted (dietary), chronic dietary rapamycin administration (pharmacologic), crowded litter (epigenetic), and Snell dwarf mice (genetic). These findings and concurrent projects using these methodologies led to three first-authored and four co-authored publications, as well as a co-authored review. For my postdoctoral training with Dr. Zhen Yan, I complemented my previous training in anabolic mechanisms of proteostasis by focusing on a catabolic mechanism of proteostatic maintenance, specifically mitochondrial autophagy (mitophagy). Using a novel fluorescent reporter gene (pmitotimer), I have elucidated a mechanism of how exercise promotes mitophagy during the recovery period in skeletal muscle in vivo, which is currently in revision (A3) with Nature Communications. This work also demonstrated that in skeletal muscle, the mitophagy regulator Ulk1 is required for metabolic adaptation to exercise training. Building upon these findings in preparation for a K99/R00 proposal, I have discovered that AMPK is uniquely localized on the mitochondria in skeletal muscle where it is responsible for regulating exerciseinduced mitophagy. Combined with additional data from our laboratory of novel Atg s that regulate mitochondrial quality, mobility, and lifespan in d. melanogaster fly muscle, position me for development of a novel and impactful independent research program upon transitioning to independence investigating skeletal muscle mitophagy s role in regulating the capacity for healthy aging through exercise in mice. Mastering the proposed techniques of FLIM microscopy and proteomic approaches for measuring post-translational protein modification and identification of individually degraded proteins complement my previous experience and existing skillset. Collectively, my technical expertise in assessing both anabolic and catabolic mechanisms of proteostasis in skeletal muscle in vivo and the scientific and professional development activities during the K99/R00 award provides me with a solid foundation and unique skill-set upon which to establish an independent research program and be competitive for future NIH-funded grants in an increasingly important area of study.

2 B. Professional Positions ACTIVITY/ OCCUPATION START DATE (mm/yy) ENDING DATE (mm/yy) FIELD INSTITUTION/ COMPANY SUPERVISOR/ EMPLOYER Graduate Research 08/08 05/10 Exercise Physiology West Virginia David L. Williamson, Ph.D. Graduate Teaching 05/10 05/11 Human Bioenergetics Colorado State Benjamin F. Miller & Karyn L. Hamilton, Ph.D. s Graduate Research 05/11 05/14 Human Bioenergetics Colorado State Benjamin F. Miller & Karyn L. Hamilton, Ph.D. s Postdoctoral Fellow 06/14 - Molecular Physiology of Virginia Zhen Yan, Ph.D. Academic and Professional Honors Outstanding Masters Student Thesis Track, West Virginia, 2010 Programs for Research and Scholarly Excellence Fellowship, Colorado State, Mouse Metabolic Phenotyping Centers Consortium (MMPC) Scholarship, 6 th Annual NIDDK/MMPC Course on Isotope Tracers in Metabolic Research, 03/11-15/2013, Little Rock, AR American College of Sports Medicine Foundation Doctoral Student Research Grant. ACSM Title: Sex and tissue differences with chronic rapamycin induction of autophagy and mitophagy. 07/ /2014. Robert M. Byrd Cardiovascular Research Center Training Grant Post-Doctoral Fellowship (NIH-NHLBI-T32), of Virginia School of Medicine, Charlottesville, VA W.M. Keck Center for Cellular Imaging 14 th Annual Workshop on FRET and FLIM Microscopy, 03/9-13/2015, of Virginia, Charlottesville, VA National Institute of Diabetes, Digestive, and Kidney Diseases (NIDDK) Post-Doctoral Fellowship Award (NIH- NIDDK-F32). Title: AMPK in Exercise-induced Mitophagy. Impact Score: 20 (awarded but declined). American Diabetes Association Post-Doctoral Fellowship Award PDF-030. Title: AMPK in Exerciseinduced Mitophagy. 01/01/ /31/2018 American Diabetes Association 3 rd Annual Focus on Fellows, 06/09-10/2016, New Orleans, LA. National Institute on Aging (NIA) Butler-Williams Scholar, 2016, Bethesda, MD. Professional Society Memberships and Leadership Experience American Heart Association American Diabetes Association American Physiological Society Invited Speaker: ACSM-Rocky Mountain Chapter Annual Meeting, Denver, CO. Title: Sex-differences in models of longevity: implications for exercise in healthy aging. 04/2014. Selected Chair: Mock Study Section Review Panel, of Virginia, Cardiovascular Research Center Training Grant. 12/2014. Invited Panelist and Chair: Career Development: Transitions from grad to post-doc and beyond. Vasculata Conference, North American Vascular Biology Organization, Charlottesville, VA. 08/2015. Selected Presentation Award: Advances in Skeletal Muscle Biology in Health & Disease Conference, Gainsville, FL. Title: Skeletal muscle Ulk1 is required for metabolic adaptation to exercise training. 03/2017. Invited Speaker: The Modulation of Aging Through Altered Proteostasis symposia at Experimental Biology

3 Conference, APS & PS, Chicago, IL. Title: Mitophagy s role in maintaining mitochondrial proteostasis and metabolic health. 04/2017. Includes invited review on the same topic to be published in J Physiol. Requested reviewer for the following journals: Journal of Applied Physiology European Journal of Sport Science Human Genetics Diabetes C. Contributions to Science Organized into three time periods: I. M.S. Training; II. Ph.D. Training; and III. Post-doctoral Training. I. M.S. Training: As a Master s student, my research focused on the dysregulation of mrna translation that is present in obese and type II diabetic subjects. Dysregulation of mrna translation is proposed to limit the adaptation that can occur as a result of exercise training, thus limiting the health benefits of exercise in obese patients and contributing to sarcopenic obesity. By inhibiting mtorc1-dependent mrna translation, through administration of the AMPK agonists AICAR and β-gpa to a mouse model of obesity and type II diabetes (ob/ob), I demonstrated that translation initiation complex formation was normalized in skeletal muscle. I hypothesized that normalizing translation may allow for proper adaptation to exercise training. Research papers Drake, J.C., Alway, S.E., Hollander, J.M., Williamson, D.L AICAR normalizes obesity-induced dysregulation of TORC1 signaling and translational capacity in fasted skeletal muscle. Am J Physiol Regul Integr Comp Physiol. 299, R1546-R1554. Drake,J.C., Benninger, L., Williamson, D.L weeks of â-gpa treatment reduces body mass while positively altering translation initiation in obese skeletal muscle. J Obes Weight Loss Ther. 1: e101. Williamson, D.L., Drake, J.C Normalizing a hyperactive mtor initiates muscle growth during obesity. Aging (Albany NY). 3, Abstracts Williamson, D.L., Drake, J.C. AICAR treatment alters skeletal muscle mass regulatory processes in ob/ob mice. Abstract for poster presentation, 14 th International Conference Biochemistry of Exercise, Guelph, ON, Canada. May Drake, J.C., Benninger, L., Alway, S.E., Williamson, D.L. Long term AMPK activation limits obesity induced muscle atrophy. Abstract for poster presentation, National American College of Sports Medicine Conference (ACSM), Denver, CO. May 2011 II. Ph.D. Training: As a Ph.D. student, my research focused on finding common mechanisms for slowed aging across several growth-restricted mouse models of long life. Using the stable isotope deuterium oxide, I helped develop a novel method for measuring sub-cellular proteostasis through simultaneously measuring new protein and new DNA synthesis rates across multiple tissues. I demonstrated a common signature of increased proteostatic mechanisms in differing models of long life across multiple tissues that did not share commonalities in markers of anabolic signaling. Collectively, this work challenged the paradigm that a reduction in anabolic signaling, specifically mtorc1, was required for slowed aging in long-lived models. Research papers Miller, B.F., Robinson M.M., Reuland, D.J., Drake, J.C., Peelor F.F., Bruss, M.D., Hellerstein, M.K., Hamilton, K.L Calorie restriction does not increase short-term or long-term protein synthesis. J Gerontol A Biol Sci Med Sci. 68: Drake, J.C., Peelor, F.F., Biela, L.M., Watkins, M.K., Miller, R.A., Hamilton, K.L., Miller, B.F Assessment of mitochondrial biogenesis and mtorc1 signaling during chronic rapamycin feeding in male and female mice. J Gerontol A Biol Sci Med Sci. 68:

4 Drake, J.C., Peelor, F.F., Biela, L.M., Miller, R.A., Hamilton, K.L., Miller, B.F Long-lived crowded litter mice have an age-dependent increase in protein synthesis to DNA synthesis and mtorc1-substrate phosphorylation. Am J Physiol Regul Endo Metab. 307: E Drake, J.C., Bruns, D.R., Peelor, F.F., Biela, L.M., Miller, R.A., Hamilton, K.L., Miller, B.F Long-lived Snell dwarf mice display increased proteostatic mechanisms that are not dependent on decreased mtorc1 activity. Aging Cell. 14: Bruns, D.R., Drake, J.C., Biela, L.M., Peeler, F.F., Miller, B.F., Hamilton, K.L Nrf2 Signaling and the slowed aging phenotype: Evidence from long-lived models. Oxid Med Cell Longev Miller, B.F. Drake, J.C., Naylor, B., Price, J.C., Hamilton, K.L Assessing proteostasis for studies of slowed aging. Ageing Res Rev. 18C, Abstracts Drake, J.C., Peelor, F.F., Biela, L.M., Miller, R.A., Hamilton, K.L., Miller, B.F. Chronic rapamycin administration maintains mitochondrial protein synthesis in heart and skeletal muscle. Abstract for poster presentation, Experimental Biology, APS, San Diego, CA. Apr FASEB J Mar 29, : Drake, J.C., Peelor, F.F., Biela, L.M., Miller, R.A., Hamilton, K.L., Miller, B.F. Maintained mitochondrial protein synthesis in hearts of Snell dwarf mice. Abstract for poster presentation, Integrative Biology of Exercise, Westminster, CO. Oct Drake, J.C., Peelor, F.F., Biela, L.M., Miller, R.A., Hamilton, K.L., Miller, B.F. Assessment of protein synthesis and cellular proliferation in long-lived crowded litter mice. Abstract for poster presentation, Experimental Biology, APS, Boston, MA. Apr FASEB J Apr 9, : Miller, B.F., Drake, J.C., Reuland, D.J., Peelor, F.F., Biela, L.M., Miller, R.A., Hamilton, K.L. Growth versus somatic maintenance and the synthesis of new DNA in skeletal muscle cells. Abstract for poster presentation, San Antonio Stem Cell Conference, San Antonia, TX. Oct Hamilton, K.L., Drake, J.C., Reuland, D.J., Peelor, F.F., Biela, L.M., Miller, R.A., Miller, B.F. DNA synthesis in cardiac tissue: Growth and somatic maintenance in long lived models. Abstract for poster presentation, San Antonio Stem Cell Conference, San Antonia, TX. Oct Miller, B.F., Drake, J.C., Peelor, F.F., Biela, L.M., Miller, R.A., Hamilton, K.L. Protein synthesis and cellular proliferation in models of slowed aging. Abstract for poster presentation, Gerontological Society of America, New Orleans, LA. Nov III. Post-doctoral Training: As a postdoctoral fellow, I have branched out into a new area of proteostasis mitophagy. Thus far, my work has filled the gap of how acute exercise promotes mitophagy in skeletal muscle. We have demonstrated that acute exercise-induced mitophagy is dependent upon the AMPK-Ulk1 cascade and that mitophagy occurs during the recovery period, several hours after the initial signaling events. Also, we demonstrate a novel role of Ulk1 in targeting of the lysosome to mitochondria for mitophagy to occur. I also demonstrated that skeletal muscle Ulk1 is required for metabolic adaptation to exercise training. This work is currently in revision (A3) with Nature Communications. My other work in the lab has uncovered a novel association of AMPK with the mitochondrial reticulum in skeletal muscle and that its activity at mitochondria is required for mitochondrial quality and exercise-induced mitophagy, which will result in an additional first authored publication. The implications of these findings for the recognition of damaged regions of the mitochondrial reticulum, aging biology, and potential for exercise training to mitigate the age-associated loss in mitophagy are the basis of my forth-coming K99/R00 application to be submitted February Research Papers ( * denotes shared authorship) Laker, R.C.*, Drake, J.C.*, Wilson, R.J., Lira, V.A., Lewellen, B.M. Zhang, M., Yan, Z. AMPK phosphorylation of Ulk1 is required for lysosome targeting to damaged mitochondria following acute exercise. (Accepted in principle Nat Commun) Drake, J.C., Wilson, R.J., Yan, Z Molecular mechanisms for mitochondrial adaptation in skeletal muscle to exercise training. FASEB J. 30:

5 Abstracts Drake, J.C., Laker, R.C., Lira, V.A., Wilson, R.J., Lewellen, B., Yan, Z. AMPK phosphorylation of Ulk1 is required for removal of damaged mitochondria via mitophagy following acute exercise. Abstract for poster presentation, 6 th International Conference on Nutrition and Physical Activity (NAPA), Taipei, Taiwan. Oct Wilson, R.J., Drake, J.C., Zhang, M, Yan, Z. ULK1-mediated autophagy is required for skeletal muscle recovery from acute ischemia-reperfusion injury. Abstract for poster presentation, Experimental Biology, APS, San Diego, CA. Apr Drake, J.C., Wilson, R.J., Laker, R.C., Zhang, M., Yan, Z. Skeletal muscle Ulk1 is required for metabolic adaptation to exercise training. Abstract selected for oral presentation, Advances in Skeletal Muscle Biology in Health & Disease Conference, Myology Institute, of Florida, Gainsville, FL. Mar (selected for formal presentation) Complete List of Published Work in MyBibliography: ascending D. Research Support American College of Sports Medicine (ACSM) ACSM Drake (PI) 07/01/13-07/01/14 Sex and tissue differences with chronic rapamycin induction of autophagy and mitophagy. Total Amount: $5, National Institute of Heart, Lung, and Blood (NHLBI) T32: HL Drake (trainee) 06/02/14-12/31/15 Role: Trainee Total Amount: Salary American Diabetes Association (ADA) ADA: 1-16-PDF-030 Drake (PI) 01/01/16-12/31/18 Title: AMPK in Exercise Induced Mitophagy Total Amount: $166, National Institute of Diabetes, Digestive, and Kidney (NIDDK) F32 (Impact Score: 20) Drake (PI) Awarded but declined Title: AMPK in Exercise Induced Mitophagy F. Mentorship Committee Sponsor: Zhen Yan, PhD zy3m@eservices.virginia.edu (434) Co-Mentors: Ammasi Periasamy, PhD ap3t@virginia.edu (434) K. Sreekumaran Nair, MD, PhD nair.sree@mayo.edu (507) P. Darrell Neufer, PhD neuferp@ecu.edu (252)