Nampt activator P7C3 ameliorates diabetes and improves skeletal muscle function modulating cell metabolism and lipid mediators
Open accessAbstract
Background: Nicotinamide phosphoribosyltransferase (Nampt), a key enzyme in NAD salvage pathway is decreased in metabolic diseases, and its precise role in skeletal muscle function is not known. We tested the hypothesis, Nampt activation by P7C3 (3,6‐dibromo‐α‐[(phenylamino)methyl]‐9H‐carbazol‐9‐ethanol) ameliorates diabetes and muscle function. Methods: We assessed the functional, morphometric, biochemical, and molecular effects of P7C3 treatment in skeletal muscle of type 2 diabetic (db/db) mice. Nampt+/− mice were utilized to test the specificity of P7C3. Results: Insulin resistance increased 1.6‐fold in diabetic mice compared with wild‐type mice and after 4 weeks treatment with P7C3 rescued diabetes (P < 0.05). In the db‐P7C3 mice fasting blood glucose levels decreased to 0.96‐fold compared with C57Bl/6J wild‐type naïve control mice. The insulin and glucose tolerance tests blood glucose levels were decreased to 0.6‐fold and 0.54‐folds, respectively, at 120 min along with an increase in insulin secretion (1.76‐fold) and pancreatic β‐cells (3.92‐fold) in db‐P7C3 mice. The fore‐limb and hind‐limb grip strengths were increased to 1.13‐fold and 1.17‐fold, respectively, together with a 14.2‐fold increase in voluntary running wheel distance in db‐P7C3 mice. P7C3 treatment resulted in a 1.4‐fold and 7.1‐fold increase in medium‐sized and larger‐sized myofibres cross‐sectional area, with a concomitant 0.5‐fold decrease in smaller‐sized myofibres of tibialis anterior (TA) muscle. The transmission electron microscopy images also displayed a 1.67‐fold increase in myofibre diameter of extensor digitorum longus muscle along with 2.9‐fold decrease in mitochondrial area in db‐P7C3 mice compared with db‐Veh mice. The number of SDH positive myofibres were increased to 1.74‐fold in db‐P7C3 TA muscles. The gastrocnemius and TA muscles displayed a decrease in slow oxidative myosin heavy chain type1 (MyHC1) myofibres expression (0.46‐fold) and immunostaining (6.4‐fold), respectively. qPCR analysis displayed a 2.9‐fold and 1.3‐fold increase in Pdk4 and Cpt1, and 0.55‐fold and 0.59‐fold decrease in Fgf21 and 16S in db‐P7C3 mice. There was also a 3.3‐fold and 1.9‐fold increase in Fabp1 and CD36 in db‐Veh mice. RNA‐seq differential gene expression volcano plot displayed 1415 genes to be up‐regulated and 1726 genes down‐regulated (P < 0.05) in db‐P7C3 mice. There was 1.02‐fold increase in serum HDL, and 0.9‐fold decrease in low‐density lipoprotein/very low‐density lipoprotein ratio in db‐P7C3 mice. Lipid profiling of gastrocnemius muscle displayed a decrease in inflammatory lipid mediators n‐6; AA (0.83‐fold), and n‐3; DHA (0.69‐fold) and EPA (0.81‐fold), and a 0.66‐fold decrease in endocannabinoid 2‐AG and 2.0‐fold increase in AEA in db‐P7C3 mice. Conclusions: Overall, we demonstrate that P7C3 activates Nampt, improves type 2 diabetes and skeletal muscle function in db/db mice.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Aging and obesity/diabetes share physiological aspects including accumulation of ectopic lipids and lipotoxicity in liver, skeletal muscle and heart, as well as decreased mitochondrial number and activity.
“A number of physiological aspects of aging are also found in obesity and diabetes (Fig. 2) including accumulation of ectopic lipids and lipotoxicity in metabolic organs such as liver, skeletal muscle and heart, as well as decreased mitochondrial number and activity [144–147].”
From Targeting Intramyocellular Lipids to Improve Aging Muscle Function (2025) · cites this paper as [145]
Administration of P7C3, a NAMPT activator, increases NAD+, enhances voluntary strength and muscle contractility, and realigns pro- and anti-inflammatory lipids in a murine model of type 2 diabetes to better approximate healthy control mice.
“We have found that administration of 3,6-dibromo-α-[(phenylamino)methyl]-9 H-carbazol-9-ethanol (P7C3), a NAMPT activator, increases NAD+, enhances voluntary strength and muscle contractility [145] (in response to direct stimulation), and realigns pro-and anti-inflammatory lipids in a murine model of type 2 diabetes to better approximate those of healthy control mice”
From Targeting Intramyocellular Lipids to Improve Aging Muscle Function (2025) · cites this paper as [145]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
An automated method for finding molecular complexes in large protein interaction networks
Bader, G. D., & Hogue, C. W. V. (2003) · BMC Bioinformatics · doi:10.1186/1471-2105-4-2 · Cited by 6,112 · see citing works
Pathophysiology of type 2 diabetes mellitus
Galicia-Garcia, U., Benito-Vicente, A., Jebari, S., Larrea-Sebal, A., Siddiqi, H., Uribe, K. B., Ostolaza, H., & Martín, C. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21176275 · Cited by 3,360 · see citing works
Mitochondrial dysfunction and type 2 diabetes
Lowell, B. B., & Shulman, G. I. (2005) · Science · doi:10.1126/science.1104343 · Cited by 2,070 · see citing works
Triglycerides and cardiovascular disease
Nordestgaard, B. G., & Varbo, A. (2014) · The Lancet · doi:10.1016/s0140-6736(14)61177-6 · Cited by 1,419 · see citing works
Yoshino, J., Mills, K. F., Yoon, M. J., & Imai, S.-I. (2011) · Cell Metabolism · doi:10.1016/j.cmet.2011.08.014 · Cited by 1,340 · see citing works
Nampt/PBEF/Visfatin Regulates Insulin Secretion in β Cells as a Systemic NAD Biosynthetic Enzyme
Revollo, J. R., Körner, A., Mills, K. F., Satoh, A., Wang, T., Garten, A., Dasgupta, B., Sasaki, Y., Wolberger, C., Townsend, R. R., et al. (2007) · Cell Metabolism · doi:10.1016/j.cmet.2007.09.003 · Cited by 911 · see citing works
Lipids and Lipoproteins in Patients With Type 2 Diabetes
Krauss, R. M. (2004) · Diabetes Care · doi:10.2337/diacare.27.6.1496 · Cited by 755 · see citing works
Physiological and pathophysiological roles of NAMPT and NAD metabolism.
Garten, A., Schuster, S., Penke, M., Gorski, T., de Giorgis, T., & Kiess, W. (2015) · Nature Reviews Endocrinology · doi:10.1038/nrendo.2015.117 · Cited by 708 · see citing works
Sarcopenia and type 2 diabetes mellitus: a bidirectional relationship
Mesinovic, J., Zengin, A., de Courten, B. V., Ebeling, P. R., & Scott, D. S. (2019) · Diabetes Metabolic Syndrome and Obesity · doi:10.2147/dmso.s186600 · Cited by 584 · see citing works
Inflammation Is Necessary for Long-Term but Not Short-Term High-Fat Diet–Induced Insulin Resistance
Lee, Y. S., Li, P., Huh, J. Y., Hwang, I. J., Lu, M., Kim, J. I., Ham, M., Talukdar, S., Chen, A., Lu, W. J., et al. (2011) · Diabetes · doi:10.2337/db11-0194 · Cited by 566 · see citing works
The Role of Skeletal Muscle Glycogen Breakdown for Regulation of Insulin Sensitivity by Exercise
Jensen, J., Rustad, P. I., Kolnes, A. J., & Lai, Y.-C. (2011) · Frontiers in Physiology · doi:10.3389/fphys.2011.00112 · Cited by 412 · see citing works
Loss of NAD Homeostasis Leads to Progressive and Reversible Degeneration of Skeletal Muscle
Frederick, D. W., Loro, E., Liu, L., Davila, A., Chellappa, K., Silverman, I. M., Quinn, W. J., Gosai, S. J., Tichy, E. D., Davis, J. G., et al. (2016) · Cell Metabolism · doi:10.1016/j.cmet.2016.07.005 · Cited by 367 · cited 1× · see citing works
“Muscle-specific knockdown of Nampt in mice reduces the intramuscular NAD levels and causes myofibre degeneration and loss of physical functions like strength and endurance capacity mimicking type 2 diabetes in humans.(21) Furthermore, knockdown of Nampt in mouse C2C12 myoblasts also reduces the NAD levels and results…”
BackgroundAssessing the impact of complications on the costs of Type II diabetes
Williams, R., Gaal, L. V., & Lucioni, C. (2002) · Diabetologia · doi:10.1007/s00125-002-0859-9 · Cited by 352 · see citing works
Discovery of a Proneurogenic, Neuroprotective Chemical
Pieper, A. A., Xie, S., Capota, E., Estill, S. J., Zhong, J., Long, J. M., Becker, G. L., Huntington, P. J., Goldman, S. E., Shen, C.-H., et al. (2010) · Cell · doi:10.1016/j.cell.2010.06.018 · Cited by 350 · see citing works
The role of intramuscular lipid in insulin resistance
Hegarty, B. D., Furler, S. M., Ye, J.-M., Cooney, G. J., & Kraegen, E. W. (2003) · Acta Physiologica Scandinavica · doi:10.1046/j.1365-201x.2003.01162.x · Cited by 256 · see citing works
P7C3 Neuroprotective Chemicals Function by Activating the Rate-Limiting Enzyme in NAD Salvage
Wang, G., Han, T., Nijhawan, D., Theodoropoulos, P., Naidoo, J., Yadavalli, S., Mirzaei, H., Pieper, A. A., Ready, J. M., & McKnight, S. L. (2014) · Cell · doi:10.1016/j.cell.2014.07.040 · Cited by 243 · see citing works
Diabetes and Cancer: a Review of Current Knowledge
Wojciechowska, J. K., Krajewski, W. R., Bolanowski, M., Kr̨ecicki, T., & Zatoński, T. (2016) · Experimental and Clinical Endocrinology & Diabetes · doi:10.1055/s-0042-100910 · Cited by 212 · see citing works
Type 2 Diabetes Mellitus and Skeletal Muscle Metabolic Function
Phielix, E., & Mensink, M. (2008) · Physiology & Behavior · doi:10.1016/j.physbeh.2008.01.020 · Cited by 198 · see citing works
Human Adipocytes Induce Inflammation and Atrophy in Muscle Cells During Obesity
Pellegrinelli, V., Rouault, C., Rodríguez‐Cuenca, S., Albert, V., Edom‐Vovard, F., Vidal‐Puig, A., Clément, K., Butler-Browne, G. S., & Lacasa, D. (2015) · Diabetes · doi:10.2337/db14-0796 · Cited by 197 · see citing works
Muscle dysfunction in type 2 diabetes: a major threat to patient’s mobility and independence
Bianchi, L., & Volpato, S. (2016) · Acta Diabetologica · doi:10.1007/s00592-016-0880-y · Cited by 175 · see citing works
Adolescent Obesity and Early-Onset Type 2 Diabetes
Twig, G., Zucker, I., Afek, A., Cukierman-Yaffe, T., Bendor, C. D., Derazne, E., Lutski, M., Shohat, T., Mosenzon, O., Tzur, D., et al. (2020) · Diabetes Care · doi:10.2337/dc19-1988 · Cited by 161 · see citing works
Cannabinoids Inhibit Insulin Receptor Signaling in Pancreatic β-Cells
Kim, W., Doyle, M. E., Liu, Z., Lao, Q., Shin, Y., Carlson, O. D., Kim, H. S., Thomas, S., Napora, J. K., Lee, E. K., et al. (2011) · Diabetes · doi:10.2337/db10-1550 · Cited by 126 · see citing works
Antonetti, D. A., Reynet, C., & Kahn, C. R. (1995) · Journal of Clinical Investigation · doi:10.1172/jci117790 · Cited by 120 · see citing works
de Guia, R. M., Agerholm, M., Nielsen, T. S., Consitt, L. A., Søgaard, D., Helge, J. W., Larsen, S., Brandauer, J., Houmard, J. A., & Treebak, J. T. (2019) · Physiological Reports · doi:10.14814/phy2.14139 · Cited by 99 · see citing works
PPARs and Microbiota in Skeletal Muscle Health and Wasting
Manickam, R., Duszka, K., & Wahli, W. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21218056 · Cited by 98 · see citing works
Self-citationHDL-cholesterol and cardiovascular disease: rethinking our approach
Siddiqi, H. K., Kiss, D., & Rader, D. (2015) · Current Opinion in Cardiology · doi:10.1097/hco.0000000000000211 · Cited by 77 · see citing works
Relationship Between Cerebrospinal Fluid Visfatin (PBEF/Nampt) Levels and Adiposity in Humans
Hallschmid, M., Randeva, H. S., Tan, B. K., Kern, W., & Lehnert, H. (2008) · Diabetes · doi:10.2337/db08-1176 · Cited by 75 · see citing works
Skeletal muscle and insulin sensitivity: pathophysiological alterations
Ryder, J. (2001) · Frontiers in bioscience · doi:10.2741/ryder · Cited by 73 · see citing works
Liu, L., Simon, B., Shi, J., Mallhi, A. K., & Eisen, H. J. (2016) · World Journal of Diabetes · doi:10.4239/wjd.v7.i18.449 · Cited by 67 · see citing works
Badole, S. L., & Bodhankar, S. L. (2010) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2010.01.019 · Cited by 55 · see citing works
Self-citationCirillo, E., Kutmon, M., Hernández, M. A. G., Hooimeijer, T., Adriaens, M. E., Eijssen, L., Parnell, L. D., Coort, S. L., & Evelo, C. T. (2018) · PLoS ONE · doi:10.1371/journal.pone.0193515 · Cited by 55 · see citing works
Mitochondrial fat oxidation is essential for lipid-induced inflammation in skeletal muscle in mice
Warfel, J. D., Bermudez, E. M., Mendoza, T. M., Ghosh, S., Zhang, J., Elks, C. M., Mynatt, R., & Vandanmagsar, B. (2016) · Scientific Reports · doi:10.1038/srep37941 · Cited by 50 · see citing works
Network-based target ranking for polypharmacological therapies
Vitali, F., Mulas, F., Marini, P., & Bellazzi, R. (2013) · Journal of Biomedical Informatics · doi:10.1016/j.jbi.2013.06.015 · Cited by 48 · see citing works
Macrovascular complications of metabolic syndrome: an early intervention is imperative
Tenenbaum, A., Motro, M., Schwammenthal, E., & Fisman, E. Z. (2004) · International Journal of Cardiology · doi:10.1016/j.ijcard.2003.07.033 · Cited by 47 · see citing works
Type 2 diabetes and obesity induce similar transcriptional reprogramming in human myocytes
Väremo, L., Henriksen, T. I., Scheele, C. C., Broholm, C., Pedersen, M., Uhlén, M., Pedersen, B. K., & Nielsen, J. (2017) · Genome Medicine · doi:10.1186/s13073-017-0432-2 · Cited by 44 · see citing works
Agerholm, M., Dall, M., Jensen, B. A. H., Prats, C., Madsen, S., Basse, A. L., Graae, A.-S., Risis, S., Goldenbaum, J., Quistorff, B., et al. (2017) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00213.2017 · Cited by 43 · see citing works
Hua, X., Sun, D., Zhang, W., Fu, J., Tong, J., Sun, S., Zeng, F., Ouyang, S., Zhang, G., Wang, S., et al. (2020) · British Journal of Pharmacology · doi:10.1111/bph.15008 · Cited by 40 · see citing works
Gu, C., Zhang, Y., Hu, Q., Wu, J., Ren, H., Liu, C., & Wang, G. (2017) · Cell Death and Disease · doi:10.1038/cddis.2017.250 · Cited by 39 · see citing works
High level of oxygen treatment causes cardiotoxicity with arrhythmias and redox modulation
Chapalamadugu, K. C., Panguluri, S. K., Bennett, E. S., Kolliputi, N., & Tipparaju, S. M. (2014) · Toxicology and Applied Pharmacology · doi:10.1016/j.taap.2014.10.019 · Cited by 36 · see citing works
Self-citationSkeletal muscle in the diabetic mouse: Histochemical and morphometric analysis
Klueber, K. M., Feczko, J. D., Schmidt, G., et al. (1989) · The Anatomical Record · doi:10.1002/ar.1092250107 · Cited by 30 · see citing works
Shochat, C., Wang, Z., Mo, C.-L., Nelson, S., Donaka, R., Huang, J., Karasik, D., & Brotto, M. (2020) · Endocrinology · doi:10.1210/endocr/bqaa189 · Cited by 25 · see citing works
Self-citationBenefits of Enhancing Nicotinamide Adenine Dinucleotide Levels in Damaged or Diseased Nerve CellsPreprint
Pieper, A. A., & McKnight, S. L. (2018) · Cold Spring Harbor Symposia on Quantitative Biology · doi:10.1101/sqb.2018.83.037622 · Cited by 21 · see citing works
Shen, Z., Chen, Q., Ying, H., Ma, Z., Bi, X., Li, X., Wang, M., Jin, C., Lai, D., Zhao, Y., et al. (2019) · Experimental and Therapeutic Medicine · doi:10.3892/etm.2019.8239 · Cited by 18 · see citing works
Marrelli, M. T., Wang, Z., Huang, J., & Brotto, M. A. P. (2020) · Malaria Journal · doi:10.1186/s12936-020-03332-3 · Cited by 13 · see citing works
Self-citationInsulin-resistance and lipoprotein abnormalities.
Fruchart, J. C. (1991) · PubMed · Cited by 9 · see citing works
Alshahrani, A. S., Al-Dubayee, M., Zahra, M., Alsebayel, F. M., Alammari, N., Alsudairy, F. A., Almajed, M., & Aljada, A. (2019) · Diabetes Metabolic Syndrome and Obesity · doi:10.2147/dmso.s228591 · Cited by 9 · see citing works
Physiological role of Kvβ2 ( AKR 6) in murine skeletal muscle growth and regulation
Chapalamadugu, K. C., Tur, J., Badole, S. L., Kukreja, R. C., Brotto, M. A. P., & Tipparaju, S. M. (2018) · Acta Physiologica · doi:10.1111/apha.13083 · Cited by 8 · see citing works
Self-citationRomić, S., Kršková, K., Olszanecki, R., Balážová, L., Lóry, V., Korićanac, G., Slamková, M., & Zórad, Š. (2017) · General Physiology and Biophysics · doi:10.4149/gpb_2017010 · Cited by 5 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Deng, F., Wu, W., Fan, X., Zhong, X., Wang, N., Wang, Y., Pan, T., & Du, Y. (2023) · International Journal of Endocrinology · doi:10.1155/2023/9926462 · Cited by 26 · see citing works
Targeting Intramyocellular Lipids to Improve Aging Muscle Function
Russ, D. W., Manickam, R., & Tipparaju, S. M. (2025) · Lipids in Health and Disease · doi:10.1186/s12944-025-02622-6 · Cited by 15 · see citing works
“…H-carba-zol-9-ethanol (P7C3), a NAMPT activator, increases NAD+, enhances voluntary strength and muscle contractility [145] (in response to direct stimulation), and realigns pro-and anti-inflammatory lipids in a murine model of type 2 diabetes to better approximate…”
Self-citation
- Authors
- Manickam, R., Tur, J., Badole, S. L., Chapalamadugu, K. C., Sinha, P., Wang, Z., Russ, D. W., Brotto, M., & Tipparaju, S. M.
- Affiliations
- University of South Florida (US)
- The University of Texas at Arlington (US)
- Corresponding author
- Brotto, Marco
- Tipparaju, Srinivas M.
- ORCID
- Venue
- Journal of Cachexia, Sarcopenia and Muscle
- Publisher
- Wiley
- Published
- 2022-01-21
- Volume
- 13
- Issue
- 2
- Pages
- 1177-1196
- ISSN
- 2190-5991 (ISSN-L)
- 2190-6009
- PMC
- PMC8977983
- OpenAlex
- W4206142955
- Cited by
- 50
- References
- 48
- Citations by year
- 2026: 7 · 2025: 9 · 2024: 15 · 2023: 15 · 2022: 4
- FWCI
- 6.14
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Journal of Cachexia Sarcopenia and Muscle (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Funders
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK119066)
- Topics
- Health Sciences › Medicine › Geriatrics and Gerontology › Sirtuins and Resveratrol in Medicine
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Health Sciences › Medicine › Physiology › Adipose Tissue and Metabolism
- Keywords
- visfatin, NAD+ salvage pathway, type 2 diabetes, skeletal muscle function, insulin resistance, mitochondrial function, lipid mediators, oxidative stress, skeletal muscle atrophy, skeletal muscle fibrosis, myosin heavy chain isoforms, PDK4, carnitine palmitoyltransferase 1
- MeSH terms
- Animals, Carbazoles, Diabetes Mellitus, Experimental, Diabetes Mellitus, Type 2, Lipids, Muscle, Skeletal, Mice, Nicotinamide Phosphoribosyltransferase
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
