Role of CD38 and NAD+ metabolism in macrophages during recovery of muscle after injury in aged mice

• Project/Area Number: 20K22733
• Research Category: Grant-in-Aid for Research Activity Start-up
• Allocation Type: Multi-year Fund
• Review Section: 0802:Biomedical structure and function and related fields
• Research Institution: University of Toyama
• Principal Investigator: Nawaz Allah 富山大学, 学術研究部医学系, 助教 (80881482)
• Project Period (FY): 2020-09-11 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥2,860,000 (Direct Cost: ¥2,200,000、Indirect Cost: ¥660,000); Fiscal Year 2021: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: Stem cell / Immune cells / Myogenesis / Pharmacology / Muscle Regenration / NAD metabolism / Muscle Stem Cell / Aging / Muscle regeneration / Myoblast / Metabolimics / Muscle Regeneration

Outline of Research at the Start

In this study, I try to elucidate the role of CD38 NAD consuming enzyme and NAD+ metabolism during aging using CD38 knockout mice and metabolomics analysis. I facilitate the metabolomics approach to reveal the metabolic reprogramming in immune cells during muscle regeneration in aged CD38 KO mice.

Outline of Final Research Achievements

CD38 is NAD+ consuming enzyme that degrade NAD+ and its expression decreases with aging. CD38 is reported to contribute to the aging-related sterile inflammation and impairs systemic insulin sensitivity in aged mice. In addition, aging-induced decline in NAD+ impair skeletal muscle regeneration by inhibiting muscle stem/satellite cells differentiation into myoblast and myofibers. Therefore, we hypothesized that that inhibition of CD38 would improve the skeletal muscle repair process through maintenance of NAD + levels. In this study, we found that administration of 78c (CD38 inhibitor) enhances NAD+ levels in C2C12 myoblast and also improve differentiation of myoblasts. Further, deletion of CD38 in aged mice enhances muscle stem/satellite cells differentiation and promotes myogenesis. Taken together, we show that inhibition of CD38 improves muscle stem cell functions and ameliorates aging-related decline in muscle recovery/regeneration.

Academic Significance and Societal Importance of the Research Achievements

Clinical importance of inhibition of CD38 may serve as best therapeutic tool for patients suffering from muscle wasting disorder and age-related muscle disorders. Metabolic reprogramming in immune cells or muscle stem cells could open a new field to boost the regenerative process.

Research Products

• [Journal Article] Astaxanthin as a Novel Mitochondrial Regulator: A New Aspect of Carotenoids, beyond Antioxidants (2021)
  • Author(s): Nishida Yasuhiro、Nawaz Allah、Hecht Karen、Tobe Kazuyuki
  • Journal Title: Nutrients Volume: 14 Issue: 1 Pages: 107-107
  • DOI: 10.3390/nu14010107
• [Journal Article] Astaxanthin, a Marine Carotenoid, Maintains the Tolerance and Integrity of Adipose Tissue and Contributes to Its Healthy Functions. (2021)
  • Author(s): Nawaz A, Nishida Y, Takikawa A, Fujisaka S, Kado T, Aminuddin A, Bilal M, Jeelani I, Rahil AM, Nishimura A, Kuwano T, Watanabe Y, Igarashi Y, Okabe K, Saeed A, Manzoor A, Usui I, Yagi K, Nakagawa T, Tobe K.
  • Journal Title: Nutrients Volume: 13 Issue: 12 Pages: 4374-4374
  • DOI: 10.3390/nu13124374
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Fate of adipocyte progenitors during adipogenesis in mice fed a high-fat diet (2021)
  • Author(s): Bilal M, Nawaz A, Kado T, Rahil Aslam M, Igarashi Y, Nishimura A, Watanabe A, Kuwano T, Liu J, Miwa H, Era T, Ikuta K, Imura J, Yagi K, Nakagawa T, Fujisaka S, Tobe K.
  • Journal Title: Molecular Metabolism Volume: 54 Pages: 101328-101328
  • DOI: 10.1016/j.molmet.2021.101328
  • Peer Reviewed / Open Access
• [Journal Article] Generation and characterization of a Meflin-CreERT2 transgenic line for lineage tracing in white adipose tissue (2021)
  • Author(s): Kuwano Takahide, Izumi Hironori, Aslam Muhammad Rahil, Igarashi Yoshiko, Bilal Muhammad, Nishimura Ayumi, Watanabe Yoshiyuki, Nawaz Allah, Kado Tomonobu, Ikuta Koichi, Yamamoto Seiji, Sasahara Masakiyo, Fujisaka Shiho, Yagi Kunimasa, Mori Hisashi, Tobe Kazuyuki
  • Journal Title: PLOS ONE Volume: 16 Issue: 3 Pages: e0248267-e0248267
  • DOI: 10.1371/journal.pone.0248267
  • Peer Reviewed / Open Access
• [Journal Article] Gut microbiota, determined by dietary nutrients, drive modification of the plasma lipid profile and insulin resistance. (2021)
  • Author(s): Watanabe Y, Fujisaka S, Ikeda K, Ishikawa M, Yamada T, Nawaz A, Kado T, Kuwano T, Nishimura A, Bilal M, Liu J, Yagi K, Hase K, Tobe K.
  • Journal Title: iScience Volume: 24 Issue: 5 Pages: 102445-102445
  • DOI: 10.1016/j.isci.2021.102445
  • Peer Reviewed / Open Access
• [Journal Article] CD206+?macrophage is an accelerator of endometriotic-like lesion via promoting angiogenesis in the endometriosis mouse model (2021)
  • Author(s): Ono Yosuke、Yoshino Osamu、Hiraoka Takehiro、Sato Erina、Furue Akiko、Nawaz Allah、Hatta Hideki、Fukushi Yoshiyuki、Wada Shinichiro、Tobe Kazuyuki、Hirota Yasushi、Osuga Yutaka、Unno Nobuya、Saito Shigeru
  • Journal Title: Scientific Reports Volume: 11 Issue: 1 Pages: 853-853
  • DOI: 10.1038/s41598-020-79578-3
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] NAD+ Metabolism Regulates Preadipocyte Differentiation by Enhancing α-Ketoglutarate-Mediated Histone H3K9 Demethylation at the PPARγ Promoter (2020)
  • Author(s): Okabe Keisuke、Nawaz Allah、Nishida Yasuhiro、Yaku Keisuke、Usui Isao、Tobe Kazuyuki、Nakagawa Takashi
  • Journal Title: Frontiers in Cell and Developmental Biology Volume: 8 Pages: 586179-586179
  • DOI: 10.3389/fcell.2020.586179
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] CD206+ M2-like Macrophages are Essential for Successful Implantation. (2020)
  • Author(s): Ono Y, Yoshino O, Ushijima A, Hiraoka T, Fukui Y, Nawaz A, Hirota Y, Wada S, Tobe K, Nakashima A, Osuga Y and Saito S.
  • Journal Title: Front Immunol. Volume: 11 Pages: 557184-557184
  • DOI: 10.3389/fimmu.2020.557184
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] Role of adipose tissue-resident macrophages in the regulation of systemic insulin sensitivity. (2022)
  • Author(s): Nawaz Allah
  • Organizer: The 42nd Annual Meeting of Japan Society for the Study of Obesity in Toyama, Japan.
  • Int'l Joint Research
• [Presentation] Macrophage-derived signals regulate non-myogenic muscle progenitor activity during muscle recovery. (2022)
  • Author(s): Nawaz Allah
  • Organizer: The 42nd Annual Meeting of Japan Society for the Study of Obesity in Toyama, Japan.
  • Int'l Joint Research
• [Presentation] Anti-diabetic potential of Astaxanthin, a natural antioxidant. (2021)
  • Author(s): Nawaz Allah
  • Organizer: 1st International Virtual Summit on Medical Sociology and Public Health as a Panelist of the session “Complementary and Alternative Medicine in the Modern Era”
  • Invited
• [Presentation] 100th Anniversary of Insulin and defining features of type 2 Diabetes. (2021)
  • Author(s): Nawaz Allah
  • Organizer: 2nd International Webinar at Jinnah University for Women, Karachi, Pakistan
  • Invited
• [Presentation] Role of immune cells (macrophages) in recovery of muscle after injury. (2021)
  • Author(s): Nawaz Allah
  • Organizer: The 64th Annual Meeting of Japan Diabetes Society at Toyama, Japan
  • Int'l Joint Research
• [Presentation] Physiological role of M2-like macrophages in the regulation of adipose tissue progenitor’s proliferations. (2021)
  • Author(s): Nawaz Allah
  • Organizer: The 64th Annual Meeting of Japan Diabetes Society at Toyama, Japan
  • Int'l Joint Research
• [Presentation] Physiological role of M2-macrophages in adipose tissue and muscle. (2021)
  • Author(s): Nawaz Allah
  • Organizer: The 41st Annual Meeting of Japan Society for the Study of Obesity in Toyama, Japan.
  • Int'l Joint Research
• [Presentation] Regulatory mechanisms between macrophages and Fibro-adipogenic progenitors during muscle recovery. (2021)
  • Author(s): Nawaz A, Kado T, Bilal M, Okabe K, Watanabe Y, Aslam MR, Nishimura A, Igarashi Y, Kuwano T, Liu J, Yagi K, Fujisaka S, Nakagawa T, Tobe K.
  • Organizer: 第41回日本肥満学会・第38回日本肥満症治療学会
  • Int'l Joint Research
• [Presentation] Depletion of CD206 M2-like macrophages ameliorates insulin resistance. (2021)
  • Author(s): Nawaz A, Kado T, Bilal M, Okabe K, Watanabe Y, Aslam MR, Nishimura A, Igarashi Y, Kuwano T, Liu J, Yagi K, Fujisaka S, Nakagawa T, Tobe K.
  • Organizer: 第41回日本肥満学会・第38回日本肥満症治療学会
  • Int'l Joint Research / Invited
• [Presentation] Depletion of CD206 M2-like macrophages induces adipocyte progenitors proliferation and promotes insulin sensitivity (2020)
  • Author(s): Nawaz A, Nakagawa T, Tobe K.
  • Organizer: 2020年度富山大学杉谷地区第2回基礎・ C-CAM・臨床研究発表会
• [Presentation] Astaxanthin ameliorate insulin resistance in skeletal muscle of obese mice via activation of the AMPK pathway. (2020)
  • Author(s): Nawaz A, Nishida Y, Nakagawa T, Tobe K.
  • Organizer: The 19th International Symposium on Carotenoids
  • Int'l Joint Research / Invited
• [Presentation] Physiological role of M2-macrophages in adipose tissue and muscle. (2020)
  • Author(s): Nawaz A, Nishida Y, Kado T, Bilal M, Okabe K, Watanabe Y, Nishimura A, Igarashi I, Kuwano T, Liu J, Yagi K, Fujisaka S, Nakagawa T, Tobe K.
  • Organizer: 第63回日本糖尿病学会年次学術集会
  • Int'l Joint Research / Invited