About

Joshua C. Drake, PhD, is an Assistant Professor in the Department of Human Nutrition, Foods, and Exercise at Virginia Tech. His research focuses on the molecular mechanisms responsible for monitoring changes in cellular energy, such as energetic stress imposed by exercise or fasting, and how these mechanisms change with age. He is particularly interested in energetic sensing within skeletal muscle, which is essential for maintaining functional independence and healthy metabolism. Dr. Drake's work aims to understand how aging affects the body's capacity to respond to energy availability changes, with a specific emphasis on mitochondrial function and energetic stress responses. Dr. Drake holds a PhD in Human Bioenergetics from Colorado State University and has completed a post-doctoral fellowship at the Robert M. Berne Cardiovascular Research Center at the University of Virginia. His research has been recognized through several major awards, including NIH/NIA grants and the SJ Ritchey Research Grant. His contributions include investigating mitochondrial quality control, energetic sensing, and their implications for aging and metabolic health, with a focus on skeletal muscle. He has presented his findings at various scientific meetings and has published extensively on these topics.

Research topics

• Biochemistry
• Biology
• Endocrinology
• Cell biology
• Medicine
• Internal medicine
• Chemistry
• Neuroscience

Selected publications

• Integrative physiology of skeletal muscle for maintaining cognitive health

  The Journal of Physiology · 2025-09-07 · 3 citations

  articleOpen accessSenior authorCorresponding

  Cognitive decline and physical impairment are often linked with ageing, contributing to declines in health span and loss of independence in older adults. Pathological cognitive decline with age is largely considered to be a brain-centric challenge. However, recent findings have begun to challenge this paradigm as the health of peripheral systems, namely skeletal muscle, predict cognitive decline associated with Alzheimer's disease (AD). Loss of muscle strength (dynapenia), loss of muscle mass (sarcopenia) and associated impairment in peripheral motor nerves and neuromuscular junctions have all been shown to either precede or coincide with AD pathology in the brain. The importance for skeletal muscle is also demonstrated in its role as an endocrine organ, secreting factors like brain-derived neurotrophic factor that promote neurogenesis in the brain. In this review we summarize the importance of skeletal muscle for cognition and discuss how the health of skeletal muscle and peripheral motor nerves may be novel sentinels for AD risk.

  PublisherOA PDFDOI

• Ulk1(S555) inhibition alters nutrient stress response by prioritizing amino acid metabolism

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-07-04

  preprintOpen accessSenior authorCorresponding

  Metabolic flexibility, the capacity to adapt fuel utilization in response to nutrient availability, is essential for maintaining energy homeostasis and preventing metabolic disease. Here, we investigate the role of Ulk1 phosphorylation at serine 555 (S555), a site regulated by AMPK, in coordinating metabolic switching following short-term caloric restriction and fasting. Using Ulk1(S555A) global knock-in mice, we show loss of S555 phosphorylation impairs glucose oxidation in skeletal muscle and liver during short-term CR, despite improved glucose tolerance. Metabolomic, transcriptomic, and mitochondrial respiration analyses suggest a compensatory reliance on autophagy-derived amino acids in Ulk1(S555A) mice. These findings suggest Ulk1(S555) phosphorylation as a critical regulatory event linking nutrient stress to substrate switching. This work highlights an underappreciated role of Ulk1 in maintaining metabolic flexibility, with implications for metabolic dysfunction.

  PublisherOA PDFDOI

• Distinct endothelial gene responses to acute exercise in skeletal muscle

  American Journal of Physiology-Endocrinology and Metabolism · 2025-08-11 · 3 citations

  articleOpen access

  This study profiles the endothelial-specific transcriptional response to acute exercise at cell-type resolution. Comparative analysis with skeletal muscle fibers revealed distinct gene expression and upstream regulators. Key findings include endothelial-specific expression of exerkines, metabolic genes, and nitric oxide signaling. These results uncover a molecular basis for endothelial adaptation to exercise and suggest a potential role in mediating systemic exercise benefits.

  PublisherDOI

• Endothelial Nitric Oxide Synthase: a Critical Mediator of Fatty Acid Oxidation during Energetic Stress in Skeletal Muscle

  Free Radical Biology and Medicine · 2025-10-30

  article
  PublisherDOI

• Sex differences in voluntary running behavior between <scp>C</scp> 57 <scp>BL</scp> /6 and <scp>BALB</scp> / <scp>cJ</scp> mouse strains do not correspond to changes in <scp>VO</scp> 2 and <scp>RER</scp>

  Physiological Reports · 2025-10-01

  articleOpen accessSenior authorCorresponding

  Abstract Exercise adaptations are influenced by sex and genetic background, contributing to variability in metabolic and physiological responses. This study investigates sex and strain‐specific differences following voluntary wheel running exercise training in submaximal and maximal oxygen consumption (VO2), respiratory exchange ratio (RER), and body composition in C57BL/6 and BALB/cJ mice. Male and female mice underwent 4 weeks of voluntary wheel running, followed by sub‐maximal and maximal treadmill tests in a metabolic chamber. Results indicate differences in running volume across sexes and strains did not consistently predict changes in physiological adaptations. Female C57BL/6 mice, which ran three times more than males on average, exhibited higher submaximal VO2 compared to their male counterparts and to female BALB/cJ mice, despite no differences in RER. In contrast, male BALB/cJ mice, which ran nearly double the distance of their female counterparts, showed a modest decrease in average RER. During maximal treadmill tests, male BALB/cJ mice demonstrated enhanced endurance capacity, characterized by increased distance run and a trend towards lower RER and blood lactate levels at exhaustion, despite no significant changes in VO2 max. Regarding body composition, female C57BL/6 mice experienced a reduction in fat mass and an increase in lean mass, whereas no significant changes were observed in BALB/cJ mice of either sex. The study highlights the need to consider sex‐ and strain‐specific factors when evaluating metabolic and endurance adaptations, and suggests VO 2 testing in mice may not reflect adaptive response to voluntary wheel running.

  PublisherDOI

• Ulk1(S555) inhibition alters nutrient stress response by prioritizing amino acid metabolism

  Molecular Metabolism · 2025-11-25

  articleOpen accessSenior authorCorresponding

  Metabolic flexibility, the capacity to adapt fuel utilization in response to nutrient availability, is essential for maintaining energy homeostasis and preventing metabolic disease. Here, we investigate the role of Ulk1 phosphorylation at serine 555 (S555), a site regulated by AMPK, in coordinating metabolic switching following short-term caloric restriction and fasting. Using Ulk1(S555A) global knock-in mice, we show loss of S555 phosphorylation impairs glucose oxidation in skeletal muscle and liver during short-term CR, despite improved glucose tolerance. Metabolomic, transcriptomic, and mitochondrial respiration analyses suggest a compensatory reliance on autophagy-derived amino acids in Ulk1(S555A) mice. These findings suggest Ulk1(S555) phosphorylation as a critical regulatory event linking nutrient stress to substrate switching. This work highlights an underappreciated role of Ulk1 in maintaining metabolic flexibility, with implications for metabolic dysfunction. • Inhibition of Ulk1(S555) inhibits caloric restriction-induced increase in glucose oxidation capacity in skeletal muscle and liver. • Metabolomics and respirometry indicate Ulk1(S555A) mice readily utilize amino acids as energetic substrates. • Inhibition of Ulk1(S555) delays metabolic switching during fasting. • Evidence that amino acid metabolism Ulk1(S555A) mice is dependent upon sustained autophagy.

  PublisherDOI

• Age-dependent remodeling of the sciatic proteome in 5xFAD mice can be attenuated by exercise or donepezil treatment to maintain neuromuscular function

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-07-04

  preprintOpen accessSenior authorCorresponding

  Background: Alzheimer's disease (AD) progresses along a continuum for years to possibly decades prior to cognitive decline and clinical diagnosis. Preclinical AD is associated with neuromuscular dysfunction. We previously characterized early neuromuscular impairment prior to cognitive decline at 4 months of age in the 5xFAD mouse model of AD. However, the underlying cause(s) for peripheral nerve dysfunction leading to impaired skeletal muscle torque production are not understood, therefore limiting interventional capacity. We hypothesized that either voluntary wheel running or donepezil treatment, begun prior to neuromuscular decline, would delay manifestation of neuromuscular impairment in 5xFAD mice. Methods: Sciatic nerves from 5xFAD and wild-type (WT) mice were analyzed by tandem mass tag (TMT)-labeled proteomics at 3, 4, and 7 months to investigate proteome remodeling. Separate cohorts, using 3-month-old 5xFAD mice and WT littermates given voluntary wheel access for 4 weeks or treated with the acetylcholinesterase inhibitor donepezil to test if neuromuscular dysfunction could be attenuated. Afterwards, we assessed tibial nerve stimulated plantar flexion torque and sciatic nerve compound (motor) neuron action potential (CNAP) in-vivo at 4 months. Additionally, we performed TMT-labeled proteomics to ascertain the effect of exercise and donepezil treatments on sciatic proteome. Results: Sciatic nerves in 5xFAD mice exhibited proteomic remodeling from 3 to 4 months, particularly in pathways linked to mitochondrial turnover, calcium handling, lipid metabolism, and inflammation, coinciding with onset of neuromuscular dysfunction. Both exercise and donepezil attenuated in nerve-stimulated muscle torque and CNAP dysfunction. Both exercise and donepezil attenuated proteomic remodeling of the sciatic nerve involving mitochondrial-centric processes through both shared and independent mechanisms. Conclusions: Declines in neuromuscular function may be pre-clinical identifiers for AD that share pathway similarities with noted central effects of the pathology on the brain. Our findings highlight the importance of a systemic approach to AD pathology and importance of disease state in interventional efficacy. Graphical abstract: Created in Biorender.

  PublisherOA PDFDOI

• Interplay of ROS, mitochondrial quality, and exercise in aging: Potential role of spatially discrete signaling

  Redox Biology · 2024-09-24 · 20 citations

  reviewOpen accessSenior authorCorresponding
  PublisherDOI

• Ulk1 phosphorylation at S555 is not required for endurance training-induced improvements in exercise and metabolic capacity in mice

  Journal of Applied Physiology · 2024-06-20 · 6 citations

  articleOpen access

  We have used CRISPR/Cas9-mediated gene editing to generate Ulk1-S555A knock-in mice to show that loss of phosphorylation of Ulk1 at S555 blunted exercise-induced mitophagy and mildly impairs energy metabolism during exercise in healthy mice. However, the knock-in mice retained exercise training-mediated improvements of endurance capacity and energy metabolism during exercise. These findings suggest that exercise-induced mitophagy through Ulk1 activation is not required for the metabolic adaptation and improved exercise capacity in young, healthy mice.

  PublisherOA PDFDOI

• Mammalian mitochondrial inorganic polyphosphate (polyP) and cell signaling: Crosstalk between polyP and the activity of AMPK

  Molecular Metabolism · 2024-11-29 · 7 citations

  articleOpen access

  Inorganic polyphosphate (polyP) is an evolutionary and ancient polymer composed by orthophosphate units linked by phosphoanhydride bonds. In mammalian cells, polyP shows a high localization in mammalian mitochondria, and its regulatory role in various aspects of bioenergetics has already been demonstrated, via molecular mechanism(s) yet to be fully elucidated. In recent years, a role for polyP in signal transduction, from brain physiology to the bloodstream, has also emerged. In this manuscript, we explored the intriguing possibility that the effects of polyP on signal transduction could be mechanistically linked to those exerted on bioenergetics. To conduct our studies, we used a combination of cellular and animal models. Our findings demonstrate for the first time the intimate crosstalk between the levels of polyP and the activation status of the AMPK signaling pathway, via a mechanism involving free phosphate homeostasis. AMPK is a key player in mammalian cell signaling, and a crucial regulator of cellular and mitochondrial homeostasis. Our results show that the depletion of mitochondrial polyP in mammalian cells downregulates the activity of AMPK. Moreover, increased levels of polyP activate AMPK. Accordingly, the genetic downregulation of AMPKF0611 impairs polyP levels in both SH-SY5Y cells and in the brains of female mice. This manuscript sheds new light on the regulation of AMPK and positions polyP as a potent regulator of mammalian cell physiology beyond mere bioenergetics, paving the road for using its metabolism as an innovative pharmacological target in pathologies characterized by dysregulated bioenergetics. • Inorganic polyphosphate (polyP) is a well-conserved polymer throughout evolution, it is also understudied. • PolyP plays an important role in maintaining mammalian bioenergetics, via a molecular mechanism that still remains unknown. • Our findings show the crosstalk between polyP and the activation status of AMPK. The mechanism seems mediated by the homeostasis of free phosphate. • Increasing our understanding of the regulation of AMPK could pave the road for new approaches against bioenergetics dysregulation.

  PublisherDOI

Recent grants

• Role of skeletal muscle mitophagy in healthy aging

  NIH · $207k · 2018–2020

Frequent coauthors

• Zhen Yan

  Tianjin University

  23 shared

• Rebecca J. Wilson

  University of California, Davis

  14 shared

• Karyn L. Hamilton

  Cedars-Sinai Medical Center

  12 shared

• Benjamin F. Miller

  10 shared

• Laurie M. Biela

  Colorado State University

  10 shared

• Frederick F. Peelor

  Oklahoma Medical Research Foundation

  9 shared

• Yuntian Guan

  University of Virginia

  9 shared

• Mei Zhang

  8 shared

Education

• Post-doc in Molecular Physiology, Robert M. Berne Cardiovascular Research Center

  University of Virginia

  2018

• Ph.D. in Human Bioenergetics, Health and Exercise Science

  Colorado State University

  2014

• M.S., Exercise Physiology

  West Virginia University

  2010

• B.S., Exercise Physiology

  West Virginia University

  2007

Awards & honors

• NIH/NIA K02 Independent Scientist Award (2025)
• NIH/NIA R01 Research Project Grant (2023)
• SJ Ritchey Research Grant (2022)
• NIH/NIA R00 Pathway to Independence Award (2020)
• NIH/NIA K99 Pathway to Independence Award (2018)