Bioactive compounds from Artemisia dracunculus L. activate AMPK signaling in skeletal muscle

TY - JOUR

T1 - Bioactive compounds from Artemisia dracunculus L. activate AMPK signaling in skeletal muscle

AU - Vandanmagsar, B.

AU - Yu, Y.

AU - Simmler, C.

AU - Dang, T. N.

AU - Kuhn, P.

AU - Poulev, A.

AU - Ribnicky, D. M.

AU - Pauli, G. F.

AU - Floyd, Z. E.

N1 - Funding Information: This work was supported by the National Center for Complementary and Integrative Health and the Office of Dietary Supplements of the NIH (P50 AT-002776 and U41 AT-008706), COBRE (National Institute of General Medical Sciences 8 P20 GM-103528) and NORC (National Institute of Diabetes and Digestive and Kidney Diseases 2 P30 DK-072476) center grants. Funding Information: This work was supported by the National Center for Complementary and Integrative Health and the Office of Dietary Supplements of the NIH ( P50 AT-002776 and U41 AT-008706 ); COBRE ( National Institute of General Medical Sciences 8 P20 GM-103528 ) and NORC ( National Institute of Diabetes and Digestive and Kidney Diseases 2 P30 DK-072476 ) center grants. Publisher Copyright: © 2021 The Authors

PY - 2021/11

Y1 - 2021/11

N2 - An extract from Artemisia dracunculus L. (termed PMI-5011) improves glucose homeostasis by enhancing insulin action and reducing ectopic lipid accumulation, while increasing fat oxidation in skeletal muscle tissue in obese insulin resistant male mice. A chalcone, DMC-2, in PMI-5011 is the major bioactive that enhances insulin signaling and activation of AKT. However, the mechanism by which PMI-5011 improves lipid metabolism is unknown. AMPK is the cellular energy and metabolic sensor and a key regulator of lipid metabolism in muscle. This study examined PMI-5011 activation of AMPK signaling using murine C2C12 muscle cell culture and skeletal muscle tissue. Findings show that PMI-5011 increases Thr172-phosphorylation of AMPK in muscle cells and skeletal muscle tissue, while hepatic AMPK activation by PMI-5011 was not observed. Increased AMPK activity by PMI-5011 affects downstream signaling of AMPK, resulting in inhibition of ACC and increased SIRT1 protein levels. Selective deletion of DMC-2 from PMI-5011 demonstrates that compounds other than DMC-2 in a “DMC-2 knock out extract” (KOE) are responsible for AMPK activation and its downstream effects. Compared to 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR) and metformin, the phytochemical mixture characterizing the KOE appears to more efficiently activate AMPK in muscle cells. KOE-mediated AMPK activation was LKB-1 independent, suggesting KOE does not activate AMPK via LKB-1 stimulation. Through AMPK activation, compounds in PMI-5011 may regulate lipid metabolism in skeletal muscle. Thus, the AMPK-activating potential of the KOE adds therapeutic value to PMI-5011 and its constituents in treating insulin resistance or type 2 diabetes.

AB - An extract from Artemisia dracunculus L. (termed PMI-5011) improves glucose homeostasis by enhancing insulin action and reducing ectopic lipid accumulation, while increasing fat oxidation in skeletal muscle tissue in obese insulin resistant male mice. A chalcone, DMC-2, in PMI-5011 is the major bioactive that enhances insulin signaling and activation of AKT. However, the mechanism by which PMI-5011 improves lipid metabolism is unknown. AMPK is the cellular energy and metabolic sensor and a key regulator of lipid metabolism in muscle. This study examined PMI-5011 activation of AMPK signaling using murine C2C12 muscle cell culture and skeletal muscle tissue. Findings show that PMI-5011 increases Thr172-phosphorylation of AMPK in muscle cells and skeletal muscle tissue, while hepatic AMPK activation by PMI-5011 was not observed. Increased AMPK activity by PMI-5011 affects downstream signaling of AMPK, resulting in inhibition of ACC and increased SIRT1 protein levels. Selective deletion of DMC-2 from PMI-5011 demonstrates that compounds other than DMC-2 in a “DMC-2 knock out extract” (KOE) are responsible for AMPK activation and its downstream effects. Compared to 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR) and metformin, the phytochemical mixture characterizing the KOE appears to more efficiently activate AMPK in muscle cells. KOE-mediated AMPK activation was LKB-1 independent, suggesting KOE does not activate AMPK via LKB-1 stimulation. Through AMPK activation, compounds in PMI-5011 may regulate lipid metabolism in skeletal muscle. Thus, the AMPK-activating potential of the KOE adds therapeutic value to PMI-5011 and its constituents in treating insulin resistance or type 2 diabetes.

KW - AMPK

KW - Artemisia dracunculus

KW - Insulin resistance

KW - LKB1

KW - Skeletal muscle

UR - http://www.scopus.com/inward/record.url?scp=85115425800&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85115425800&partnerID=8YFLogxK

U2 - https://doi.org/10.1016/j.biopha.2021.112188

DO - https://doi.org/10.1016/j.biopha.2021.112188

M3 - Article

C2 - 34563947

SN - 0753-3322

VL - 143

JO - Biomedicine and Pharmacotherapy

JF - Biomedicine and Pharmacotherapy

M1 - 112188

ER -