Ursolic acid improves the indoxyl sulfate-induced impairment of mitochondrial biogenesis in C2C12 cells
2
조회
0
다운로드
0
인용
0
참고문헌
키워드
초록
BACKGROUND/OBJECTIVES: Patients with chronic kidney disease (CKD) have a high concentration of uremic toxins in their blood and often experience muscle atrophy. Indoxyl sulfate (IS) is a uremic toxin produced by tryptophan metabolism. Although an elevated IS level may induce muscle dysfunction, the effect of IS on physiological concentration has not been elucidated. Additionally, the effects of ursolic acid (UA) on muscle hypertrophy have been reported in healthy models; however, it is unclear whether UA ameliorates muscle dysfunction associated with chronic diseases, such as CKD. Thus, this study aimed to investigate whether UA can improve the IS-induced impairment of mitochondrial biogenesis. MATERIALS/METHODS: C2C12 cells were incubated with or without IS (0.1 mM) and UA (1 or 2 μM) to elucidate the physiological effect of UA on CKD-related mitochondrial dysfunction and its related mechanisms using real-time reverse transcription-polymerase chain reaction, western blotting and enzyme-linked immunosorbent assay. RESULTS: IS suppressed the expression of differentiation marker genes without decreasing cell viability. IS decreased the mitochondrial DNA copy number and ATP levels by downregulating the genes pertaining to mitochondrial biogenesis (Ppargc1a, Nrf1, Tfam, Sirt1, and Mef2c), fusion (Mfn1 and Mfn2), oxidative phosphorylation (Cycs and Atp5b), and fatty acid oxidation (Pdk4, Acadm, Cpt1b, and Cd36). Furthermore, IS increased the intracellular mRNA and secretory protein levels of interleukin (IL)-6. Finally, UA ameliorated the IS-induced impairment in C2C12 cells. CONCLUSIONS: Our results indicated that UA improves the IS-induced impairment of mitochondrial biogenesis by affecting differentiation, ATP levels, and IL-6 secretion in C2C12 cells. Therefore, UA could be a novel therapeutic agent for CKD-induced muscle dysfunction.
Abstract
BACKGROUND/OBJECTIVES: Patients with chronic kidney disease (CKD) have a high concentration of uremic toxins in their blood and often experience muscle atrophy. Indoxyl sulfate (IS) is a uremic toxin produced by tryptophan metabolism. Although an elevated IS level may induce muscle dysfunction, the effect of IS on physiological concentration has not been elucidated. Additionally, the effects of ursolic acid (UA) on muscle hypertrophy have been reported in healthy models; however, it is unclear whether UA ameliorates muscle dysfunction associated with chronic diseases, such as CKD. Thus, this study aimed to investigate whether UA can improve the IS-induced impairment of mitochondrial biogenesis. MATERIALS/METHODS: C2C12 cells were incubated with or without IS (0.1 mM) and UA (1 or 2 μM) to elucidate the physiological effect of UA on CKD-related mitochondrial dysfunction and its related mechanisms using real-time reverse transcription-polymerase chain reaction, western blotting and enzyme-linked immunosorbent assay. RESULTS: IS suppressed the expression of differentiation marker genes without decreasing cell viability. IS decreased the mitochondrial DNA copy number and ATP levels by downregulating the genes pertaining to mitochondrial biogenesis (Ppargc1a, Nrf1, Tfam, Sirt1, and Mef2c), fusion (Mfn1 and Mfn2), oxidative phosphorylation (Cycs and Atp5b), and fatty acid oxidation (Pdk4, Acadm, Cpt1b, and Cd36). Furthermore, IS increased the intracellular mRNA and secretory protein levels of interleukin (IL)-6. Finally, UA ameliorated the IS-induced impairment in C2C12 cells. CONCLUSIONS: Our results indicated that UA improves the IS-induced impairment of mitochondrial biogenesis by affecting differentiation, ATP levels, and IL-6 secretion in C2C12 cells. Therefore, UA could be a novel therapeutic agent for CKD-induced muscle dysfunction.
참고문헌 (49)
- Wang XH, "Mechanisms of muscle wasting in chronic kidney disease", Nat Rev Nephrol, 10, pp.504~516 (2014)
- Carrero JJ, "Screening for muscle wasting and dysfunction in patients with chronic kidney disease", Kidney Int, 90, pp.53~66 (2016)
- Hirai K, "Sarcopenia and physical inactivity in patients with chronic kidney disease", Nephrourol Mon, 8, pp.e37443~ (2016)
- Kim JK, "Prevalence of and factors associated with sarcopenia in elderly patients with end-stage renal disease", Clin Nutr, 33, pp.64~68 (2014)
- Souza VA, "Sarcopenia in chronic kidney disease", J Bras Nefrol, 37, pp.98~105 (2015)
- Beasley JM, "The role of dietary protein intake in the prevention of sarcopenia of aging", Nutr Clin Pract, 28, pp.684~690 (2013)
- Mandayam S, "Dietary protein restriction benefits patients with chronic kidney disease", Nephrology(Carlton), 11, pp.53~57 (2006)
- Joyner MJ, "Endurance exercise performance : the physiology of champions", J Physiol, 586, pp.35~44 (2008)
- Tadaishi M, "Skeletal muscle-specific expression of PGC-1α-b, an exercise-responsive isoform, increases exercise capacity and peak oxygen uptake", PLoS One, 6, pp.e28290~ (2011)
- Kosmadakis GC, "Physical exercise in patients with severe kidney disease", Nephron Clin Pract, 115, pp.c7~16 (2010)
- Gamboa JL, "Mitochondrial dysfunction and oxidative stress in patients with chronic kidney disease", Physiol Rep, 4, pp.e12780~ (2016)
- Rao M, "Mitochondrial DNA injury and mortality in hemodialysis patients", J Am Soc Nephrol, 20, pp.189~196 (2009)
- Fujii H, "Role of oxidative stress and indoxyl sulfate in progression of cardiovascular disease in chronic kidney disease", Ther Apher Dial, 15, pp.125~128 (2011)
- Lim CF, "A furan fatty acid and indoxyl sulfate are the putative inhibitors of thyroxine hepatocyte transport in uremia", J Clin Endocrinol Metab, 76, pp.318~324 (1993)
- Enoki Y, "Indoxyl sulfate potentiates skeletal muscle atrophy by inducing the oxidative stress-mediated expression of myostatin and atrogin-1", Sci Rep, 6, pp.32084~ (2016)
- Jäger S, "Pentacyclic triterpene distribution in various plants-rich sources for a new group of multi-potent plant extracts", Molecules, 14, pp.2016~2031 (2009)
- Lee J, "Ursolic acid ameliorates thymic atrophy and hyperglycemia in streptozotocin-nicotinamide-induced diabetic mice", Chem Biol Interact, 188, pp.635~642 (2010)
- Tsai SJ, "Antioxidative and anti-inflammatory protection of oleanolic acid and ursolic acid in PC12 cells", J Food Sci, 73, pp.H174~H178 (2008)
- Leng S, "Ursolic acid promotes cancer cell death by inducing Atg5-dependent autophagy", Int J Cancer, 133, pp.2781~2790 (2013)
- Kunkel SD, "mRNA expression signatures of human skeletal muscle atrophy identify a natural compound that increases muscle mass", Cell Metab, 13, pp.627~638 (2011)
- 방현석, "Ursolic Acid-Induced Elevation of Serum Irisin Augments Muscle Strength During Resistance Training in Men", The Korean Journal of Physiology & Pharmacology, 18(5), pp.441~446 (2014), 대한약리학회
- Zhang SZ, "Neutral red(NR)assay for cell viability and xenobiotic-induced cytotoxicity in primary cultures of human and rat hepatocytes", Cell Biol Toxicol, 6, pp.219~234 (1990)
- Duranton F, "Normal and pathologic concentrations of uremic toxins", J Am Soc Nephrol, 23, pp.1258~1270 (2012)
- Rodrigues GGC, "Indoxyl sulfate contributes to uremic sarcopenia by inducing apoptosis in myoblasts", Arch Med Res, 51, pp.21~29 (2020)
- Bentzinger CF, "Building muscle : molecular regulation of myogenesis", Cold Spring Harb Perspect Biol, 4, pp.a008342~ (2012)
- Alessi DR, "Mechanism of activation of protein kinase B by insulin and IGF-1", EMBO J, 15, pp.6541~6551 (1996)
- Ahn NG, "The MAP kinase cascade. Discovery of a new signal transduction pathway", Mol Cell Biochem, 127-128, pp.201~209 (1993)
- Westermann B, "Bioenergetic role of mitochondrial fusion and fission", Biochim Biophys Acta, 1817, pp.1833~1838 (2012)
- Ihle JN, "Cytokine receptor signalling", Nature, 377, pp.591~594 (1995)
- Kuppusamy P, "4-Hydroxy-3-methoxy cinnamic acid accelerate myoblasts differentiation on C2C12 mouse skeletal muscle cells via AKT and ERK 1", 2 activation, 2019, pp.60, 152873~
- Li X, "MicroRNA-106a-5p inhibited C2C12 myogenesis via targeting PIK3R1 and modulating the PI3K", AKT signaling, 2018, pp.9, 333~
- 김재철, "Concurrent treatment with ursolic acid and low-intensity treadmill exercise improves muscle atrophy and related outcomes in rats", The Korean Journal of Physiology & Pharmacology, 22(4), pp.427~436 (2018), 대한약리학회[DOI]
- Wagatsuma A, "Mitochondria as a potential regulator of myogenesis", Sci World J, 2013, pp.593267~ (2013)
- Avin KG, "Skeletal muscle regeneration and oxidative stress are altered in chronic kidney disease", PLoS One, 11, pp.e0159411~ (2016)
- Dai W, "Dysregulated mitochondrial dynamics and metabolism in obesity, diabetes, and cancer", Front Endocrinol(Lausanne), 10, pp.570~ (2019)
- Vásquez-Trincado C, "Mitochondrial dynamics, mitophagy and cardiovascular disease", J Physiol, 594, pp.509~525 (2016)
- Chen H, "Mitochondrial fusion is required for mtDNA stability in skeletal muscle and tolerance of mtDNA mutations", Cell, 141, pp.280~289 (2010)
- Ishihara N, "Mitochondrial fission factor Drp1 is essential for embryonic development and synapse formation in mice", Nat Cell Biol, 11, pp.958~966 (2009)
- Rugarli EI, "Mitochondrial quality control : a matter of life and death for neurons", EMBO J, 31, pp.1336~1349 (2012)
- Wu H, "Regulation of mitochondrial biogenesis in skeletal muscle by CaMK", Science, 296, pp.349~352 (2002)
- Wang D, "Dietary supplementation with ketoacids protects against CKD-induced oxidative damage and mitochondrial dysfunction in skeletal muscle of 5", 6 nephrectomised rats, 2018, pp.8, 18~
- Su. Z, "Chronic kidney disease induces autophagy leading to dysfunction of mitochondria in skeletal muscle", Am J Physiol Renal Physiol, 312, pp.F1128~F1140 (2017)
- Wu Z, "Mechanisms controlling mitochondrial biogenesis and respiration through the thermogenic coactivator PGC-1", Cell, 98, pp.115~124 (1999)
- Picca A, "Regulation of mitochondrial biogenesis through TFAM-mitochondrial DNA interactions : useful insights from aging and calorie restriction studies", Mitochondrion, 25, pp.67~75 (2015)
- Kim JC, "Inhibition of oxidative stress by antioxidant supplementation does not limit muscle mitochondrial biogenesis or endurance capacity in rats", J Nutr Sci Vitaminol(Tokyo), 63, pp.277~283 (2017)
- Tamaki M, "Chronic kidney disease reduces muscle mitochondria and exercise endurance and its exacerbation by dietary protein through inactivation of pyruvate dehydrogenase", Kidney Int, 85, pp.1330~1339 (2014)
- White JP, "IL-6 regulation on skeletal muscle mitochondrial remodeling during cancer cachexia in the ApcMin", + mouse, 2012, pp.2, 14~
- Bonetto A, "JAK", STAT3 pathway inhibition blocks skeletal muscle wasting downstream of IL-6 and in experimental cancer cachexia, 2012, pp.303, E410~E421
- Siengdee P, "MicroRNAs regulate cellular ATP levels by targeting mitochondrial energy metabolism genes during C2C12 myoblast differentiation", PLoS One, 10, pp.e0127850~ (2015)
