The major focus of Carol A. Witczak’s research laboratory is to understand the molecular and cellular factors that regulate skeletal muscle metabolism during both physiological and pathological conditions, such as exercise, type 2 diabetes, muscle wasting and menopause. We are interested in determining how genetic, nutritional, and environmental factors coordinately regulate skeletal muscle substrate uptake and utilization, resulting in differential manifestations of tissue function in both pre-clinical animal models and clinical patient populations. Our overall goal is to identify novel proteins responsible for the regulation of key metabolic processes, such as glucose uptake and protein synthesis, and then utilize that knowledge towards the development of innovative therapies for chronic human disease states such as type 2 diabetes and cachexia.
The Witczak laboratory uses a diverse range of physiological, biochemical, and genetic approaches to investigate metabolism in skeletal muscle.
The Witczak laboratory values wellness, individuality, diversity, mentoring, and professional development.
Current Research Areas
Targeting Resistance Exercise Training/Mechanical Loading-Stimulated Skeletal Muscle Glucose Uptake for the Treatment of Type 2 Diabetes
Type 2 diabetes currently afflicts >537 million adults creating an economic burden totaling >$966 billion per year. With recent epidemiological estimates projecting that 1.3 billion adults will be diagnosed with diabetes by 2050, diabetes is poised to cripple healthcare systems around the world. Type 2 diabetes is a progressive metabolic disease characterized by hyperglycemia, hyperinsulinemia, and insulin resistance in skeletal muscle, the primary site of insulin-mediated blood glucose disposal. Importantly, while insulin-stimulated muscle glucose uptake is impaired in type 2 diabetes, the ability of insulin-independent stimuli such as exercise to increase muscle glucose uptake and lower blood glucose levels remains intact. Thus, increasing muscle glucose uptake via an exercise-dependent mechanism is an effective strategy to treat hyperglycemia in type 2 diabetes. Despite this fact, the medications currently prescribed for type 2 diabetes target insulin secretion from the pancreas, hepatic glucose output, glucose excretion from the kidneys, glucose absorption from the intestines, and insulin sensitivity in adipose tissue. None of the medications currently available target exercise-dependent skeletal muscle glucose uptake.
A critical barrier in the development of new type 2 diabetes therapies that target exercise-dependent muscle glucose uptake is the identification of the intracellular proteins that govern this process. Our work has begun to address this barrier by investigating the identity of the novel glucose transporters responsible for resistance exercise training/mechanical loading-stimulated muscle glucose uptake.
Identifying Sex-Specific Factors that Control Skeletal Muscle Glucose Uptake for the Treatment of Type 2 Diabetes Following Menopause
Men and women differ dramatically in their body size, body composition (i.e., fat mass and muscle mass proportions), and susceptibility to type 2 diabetes. Intriguingly, despite having a higher percentage of body fat and a lower percentage of muscle mass, women exhibit a reduced prevalence of insulin resistance and type 2 diabetes compared to men. While the molecular mechanism underlying this fundamental sex-based difference in susceptibility to type 2 diabetes is currently unknown, studies have linked the protective effect of the female sex with higher rates of glucose uptake into skeletal muscle.
Our work has begun to address this critical knowledge gap by investigating the genetic and hormonal factors that differentially regulate skeletal muscle glucose uptake between the sexes.
Recent Publications
Negoita F, Addinsall AB, Hellberg K, Bringas CF, Hafen PS, Sermersheim TJ, Agerholm M, Lewis CTA, Ahwazi D, Ling NXY, Larsen JK, Deshmukh AS, Hossain MA, Oakhill JS, Ochala J, Brault JJ, Sankar U, Drewry DH, Scott JW, Witczak CA, Sakamoto K. CaMKK2 is not involved in contraction-stimulated AMPK activation and glucose uptake in skeletal muscle. Mol Metab. 2023 Sep;75:101761. doi: 10.1016/j.molmet.2023.101761. PMID: 37380024; PMCID: PMC10362367.
Amorese AJ, Minchew EC, Tarpey MD, Readyoff AT, Williamson NC, Schmidt CA, McMillin SL, Goldberg EJ, Terwilliger ZS, Spangenburg QA, Witczak CA, Brault JJ, Abel ED, McClung JM, Fisher-Wellman KH, Spangenburg EE. Hypoxia Resistance Is an Inherent Phenotype of the Mouse Flexor Digitorum Brevis Skeletal Muscle.Function (Oxf). 2023 Mar 21;4(3):zqad012. doi: 10.1093/function/zqad012. eCollection 2023. PMID: 37168496; PMCID: PMC10165545.
McMillin SL, Evans PL, Taylor WM, Weyrauch LA, Sermersheim TJ, Welc SS, Heitmeier MR, Hresko RC, Hruz PW, Koumanov F, Holman GD, Abel ED, Witczak CA. Muscle-Specific Ablation of Glucose Transporter 1 (GLUT1) Does Not Impair Basal or Overload-Stimulated Skeletal Muscle Glucose Uptake. Biomolecules. 2022 Nov 23;12(12):1734. doi: 10.3390/biom12121734. PMID: 36551162; PMCID: PMC9776291.
Miller SG, Hafen PS, Law AS, Springer CB, Logsdon DL, O'Connell TM, Witczak CA, Brault JJ. AMP deamination is sufficient to replicate an atrophy-like metabolic phenotype in skeletal muscle. Metabolism. 2021 Oct;123:154864. doi: 10.1016/j.metabol.2021.154864. PMID: 34400216; PMCID: PMC8453098.
McMillin SL, Stanley EC, Weyrauch LA, Brault JJ, Kahn BB, Witczak CA. Insulin Resistance Is Not Sustained Following Denervation in Glycolytic Skeletal Muscle. Int J Mol Sci. 2021 May 6;22(9):4913. doi: 10.3390/ijms22094913.PMID: 34066429; PMCID: PMC8125496.
Smith CD, Lin CT, McMillin SL, Weyrauch LA, Schmidt CA, Smith CA, Kurland IJ, Witczak CA, Neufer PD. Genetically increasing flux through β-oxidation in skeletal muscle increases mitochondrial reductive stress and glucose intolerance. Am J Physiol Endocrinol Metab. 2021 May 1;320(5):E938-E950. doi: 10.1152/ajpendo.00010.2021. PMID: 33813880; PMCID: PMC8238127.
Weyrauch LA, McMillin SL, Witczak CA. Insulin Resistance Does Not Impair Mechanical Overload-Stimulated Glucose Uptake, but Does Alter the Metabolic Fate of Glucose in Mouse Muscle. Int J Mol Sci. 2020 Jul 1;21(13):4715. doi: 10.3390/ijms21134715.PMID: 32630335; PMCID: PMC7370044.
Davis PR, Miller SG, Verhoeven NA, Morgan JS, Tulis DA, Witczak CA, Brault JJ. Increased AMP deaminase activity decreases ATP content and slows protein degradation in cultured skeletal muscle. Metabolism. 2020 Jul;108:154257. doi: 10.1016/j.metabol.2020.154257. PMID: 32370945; PMCID: PMC7319876.
Iñigo MR, Amorese AJ, Tarpey MD, Balestrieri NP, Jones KG, Patteson DJ, Jackson KC, Torres MJ, Lin CT, Smith CD, Heden TD, McMillin SL, Weyrauch LA, Stanley EC, Schmidt CA, Kilburg-Basnyat BB, Reece SW, Psaltis CE, Leinwand LA, Funai K, McClung JM, Gowdy KM, Witczak CA, Lowe DA, Neufer PD, Spangenburg EE. Estrogen receptor-α in female skeletal muscle is not required for regulation of muscle insulin sensitivity and mitochondrial regulation. Mol Metab. 2020 Apr;34:1-15. doi: 10.1016/j.molmet.2019.12.010. PMID: 32180550; PMCID: PMC6994285.
