Apigenin Enhances Skeletal Muscle Hypertrophy and Myoblast Differentiation by Regulating Prmt7
Open accessAbstract
// Young Jin Jang 1,* , Hyo Jeong Son 1,* , Yong Min Choi 1 , Jiyun Ahn 1,2 , Chang Hwa Jung 1,2 and Tae Youl Ha 1,2 1 Division of Nutrition and Metabolism Research, Korea Food Research Institute, Seongnam, Republic of Korea 2 Division of Food Biotechnology, University of Science and Technology, Daejeon, Republic of Korea * These authors have contributed equally to this work Correspondence to: Tae Youl Ha, email: // Keywords : apigenin, Prmt7, GPR56, skeletal muscle hypertrophy, myoblast differentiation, Gerotarget Received : March 24, 2017 Accepted : August 27, 2017 Published : September 16, 2017 Abstract Apigenin, a natural flavone abundant in various plant-derived foods including parsley and celery, has been shown to prevent inflammation and inflammatory diseases. However, the effect of apigenin on skeletal muscle hypertrophy and myogenic differentiation has not previously been elucidated. Here, we investigated the effects of apigenin on quadricep muscle weight and running distance using C57BL/6 mice on an accelerating treadmill. Apigenin stimulated mRNA expression of MHC (myosin heavy chain) 1, MHC2A, and MHC2B in the quadricep muscles of these animals. GPR56 (G protein-coupled receptor 56) and its ligand collagen III were upregulated by apigenin supplementation, together with enhanced PGC-1α, PGC-1α1, PGC-1α4, IGF1, and IGF2 expression. Prmt7 protein expression increased in conjunction with Akt and mTORC1 activation. Apigenin treatment also upregulated FNDC5 (fibronectin type III domain containing 5) mRNA expression and serum irisin levels. Furthermore, apigenin stimulated C2C12 myogenic differentiation and upregulated total MHC, MHC2A, and MHC2B expression. These events were attributable to an increase in Prmt7-p38-myoD expression and Akt and S6K1 phosphorylation. We also observed that Prmt7 regulates both PGC-1α1 and PGC-1α4 expression, resulting in a subsequent increase in GPR56 expression and mTORC1 activation. Taken together, these findings suggest that apigenin supplementation can promote skeletal muscle hypertrophy and myogenic differentiation by regulating the Prmt7-PGC-1α-GPR56 pathway, as well as the Prmt7-p38-myoD pathway, which may contribute toward the prevention of skeletal muscle weakness.
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Written from the paper’s full text.
TL;DR
Apigenin supplementation increased quadricep muscle weight, muscle fiber size, and treadmill running distance in male C57BL/6 mice, and promoted C2C12 myogenic differentiation. The proposed mechanism involves Prmt7-dependent regulation of PGC-1α–GPR56–mTORC1 signaling and the Prmt7–p38–MyoD pathway.
Key findings
- Mice fed 0.2% or 0.4% apigenin for 7 weeks showed dose-dependent increases in quadricep muscle weight, muscle fiber cross-sectional area, and running distance on an accelerating treadmill; tibialis anterior, gastrocnemius, triceps, total body, heart, subcutaneous fat, epididymal fat, and liver weights were not significantly altered.
- Apigenin increased quadricep mRNA expression of MHC1, MHC2A, and MHC2B; GPR56 and collagen III; total PGC-1α and PGC-1α isoforms 1 and 4; IGF1 and IGF2; and FNDC5, along with increased serum irisin. It also increased Prmt7 protein expression and Akt/mTORC1 pathway activation, including phosphorylation of S6K1, 4E-BP1, and S6.
- In C2C12 cells, apigenin at 5 µM increased the MHC-positive nucleus ratio, and myotube thickness increased dose-dependently; 2.5 µM apigenin enhanced early differentiation similarly to 10 ng/ml IGF1. Apigenin increased total MHC, MHC2A, MHC2B, MyoD, Prmt7, phospho-p38, FNDC5, and phosphorylation of Akt and S6K1.
- Prmt7 knockdown attenuated PGC-1α, PGC-1α1, PGC-1α4, GPR56, FNDC5, and phosphorylation of Akt, S6K1, and 4E-BP1; apigenin’s effects on MHC, MHC2A, MHC2B, and MyoD were reduced by siPrmt7.
Methods
- Connectivity mapping compared an aged male skeletal muscle mRNA profile (70–80 years old) with a young male profile (19–25 years old) and 1309 small molecules across human cancer cell lines; apigenin had a connectivity score of -0.465 in PC3 cells.
- Male C57BL/6 mice (5 weeks old, n = 30) were fed a modified AIN-76A diet with 0.2% apigenin (Api-L), 0.4% apigenin (Api-H), or no apigenin for 7 weeks; outcomes included quadricep H&E cross-sections, treadmill running distance, qPCR, Western blot, and serum irisin ELISA.
- C2C12 myoblasts were differentiated with 2.5 or 5 µM apigenin, with siRNA knockdown of Prmt7 or FNDC5; analyses included immunofluorescence for total MHC, qPCR, and Western blot. Statistical analysis used one-way ANOVA with Dunnett’s multiple comparison test, with p < 0.05 considered significant.
Limitations
- The paper states that further studies on the effect of apigenin in aged mouse muscle are needed to better understand its protective effect on sarcopenia.
- Evident from the text: the in vivo experiments used only male C57BL/6 mice, so sex-specific effects are not addressed.
- Evident from the text: mechanistic conclusions rely largely on C2C12 knockdown experiments and correlative signaling changes; direct apigenin–Prmt7 binding or rescue/overexpression evidence is not reported.
Model-written summary. Check it against the paper before relying on it.
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Cites
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Claims the paper makes
0 of 15 cited sources checked · 0 supported · 0 flagged
- Findingown data
Apigenin increased mRNA expression of IGF1 in mouse quadricep muscle.
“We observed that mRNA expression of IGF1 and 2 were increased by apigenin supplementation (Figure 3D).”
Quote in the paperSubstantial claim - Findingown data
Prmt7 knockdown repressed FNDC5 expression in C2C12 cells.
“FNDC5 expression was also repressed by Prmt7 knockdown (Figure 5A).”
Quote in the paperSubstantial claim - Findingown data
At the early differentiation stage, 2.5 μM apigenin enhanced myogenic differentiation similar to 10 ng/ml IGF1.
“At the early differentiation stage, 2.5 µM of apigenin enhanced myogenic differentiation similar to the effect of 10ng/ml of IGF1 (Supplementary Figure S4).”
Quote in the paperNot a substantial claim - Findingown data
Apigenin increased phosphorylation of Akt and S6K1 in C2C12 cells.
“We also found that apigenin enhances protein expression of Prmt7 (Figure 4C), and increased the phosphorylation of Akt and S6K1, substrates of mTORC1 (Figure 4D).”
Quote in the paperSubstantial claim - Findingown data
Apigenin increased FNDC5 mRNA expression in mouse quadricep muscle in the Api-H group.
“FNDC5 (fibronectin type III domain-containing protein 5) is a precursor of irisin, and the Api-H group exhibited increased FNDC5 expression and serum irisin concentrations (Figure 3F and 3G).”
Quote in the paperNot a substantial claim
- Findingown data
Apigenin increased mRNA and protein expression of GPR56 in mouse quadricep muscle.
“Apigenin increased mRNA and protein expression of GPR56 and mRNA expression of its ligand, collagen III (Figure 3B and 3E).”
- Also stated in: § Apigenin upregulates mRNA expression of MHC and GPR56 signaling in mouse quadricep muscle and increases serum irisin levels · plain
“Apigenin increases GPR56 and Col3a1 mRNA expression.”
Quote in the paperSubstantial claim - Also stated in: § Apigenin upregulates mRNA expression of MHC and GPR56 signaling in mouse quadricep muscle and increases serum irisin levels · plain
- Findingown data
Apigenin increased serum irisin concentrations in mice in the Api-H group.
“FNDC5 (fibronectin type III domain-containing protein 5) is a precursor of irisin, and the Api-H group exhibited increased FNDC5 expression and serum irisin concentrations (Figure 3F and 3G).”
Quote in the paperNot a substantial claim - Findingown data
Apigenin increased protein expression of total MHC, MHC2A, and MHC2B in C2C12 myotubes.
“Western blot analysis showed that apigenin increased protein expression of total MHC, MHC2A, and 2B (Figure 4B).”
Quote in the paperSubstantial claim - Findingown data
Apigenin increased phosphorylation of S6K1 and 4E-BP1 in mouse quadricep muscle.
“Apigenin increased phosphorylation of S6K1 and 4E-BP1, two major substrates of mTORC1.”
Quote in the paperSubstantial claim - Findingown data
Apigenin stimulated MyoD protein expression in C2C12 myotubes.
“We found that MyoD protein expression was stimulated by apigenin treatment (Figure 4B).”
Quote in the paperSubstantial claim - Findingown data
Apigenin increased mRNA expression of IGF2 in mouse quadricep muscle.
“We observed that mRNA expression of IGF1 and 2 were increased by apigenin supplementation (Figure 3D).”
Quote in the paperNot a substantial claim - Findingown data
Apigenin increased phosphorylation of p38 MAPK in C2C12 cells.
“We observed that apigenin increased phosphorylation of p38 MAPK (Figure 4C).”
Quote in the paperSubstantial claim - Findingown data
Apigenin had a connectivity score of -0.465 in the PC3 cell line.
“The connectivity score of apigenin was -0.465 in the PC3 cell line.”
Quote in the paperNot a substantial claim - Findingown data
Apigenin at 5 μM increased the nucleus ratio in C2C12 myotubes.
“Apigenin at 5µM increased the nucleus ratio in C2C12 myotubes, and myotube thickness was enhanced in a dose-dependent manner by apigenin treatment (Figure 4A).”
Quote in the paperSubstantial claim - Findingown data
Prmt7 knockdown attenuated PGC-1α expression in C2C12 cells.
“PGC-1α expression was attenuated by Prmt7 knockdown, consistent with a previous study [12].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [12] Kang, 2016, Prmt7 Deficiency Causes Reduced Skeletal Muscle Oxidative Metabolism and Age-Related Obesity, Diabetes source
Not checked in the free run.
- Findingown data
Apigenin enhanced protein expression of Prmt7 in C2C12 cells.
“We also found that apigenin enhances protein expression of Prmt7 (Figure 4C)”
Quote in the paperSubstantial claim - Findingown data
Prmt7 knockdown attenuated GPR56 expression and phosphorylation of Akt, S6K1, and 4E-BP1 in C2C12 cells.
“GPR56 expression and phosphorylation of Akt, S6K1, and 4E-BP1 were attenuated by Prmt7 knockdown (Figure 5A).”
Quote in the paperSubstantial claim - Findingown data
Apigenin enhanced myotube thickness in a dose-dependent manner in C2C12 myotubes.
“Apigenin at 5µM increased the nucleus ratio in C2C12 myotubes, and myotube thickness was enhanced in a dose-dependent manner by apigenin treatment (Figure 4A).”
Quote in the paperSubstantial claim - Findingown data
Apigenin enhanced mRNA and protein expression of total PGC-1α in mouse quadricep muscle.
“Apigenin also enhanced mRNA and protein expression of total PGC-1α, and mRNA expression of PGC-1α isoforms 1 and 4 (Figure 3C).”
Quote in the paperSubstantial claim - Findingown data
Apigenin increased mRNA expression of PGC-1α isoforms 1 and 4 in mouse quadricep muscle.
“Apigenin also enhanced mRNA and protein expression of total PGC-1α, and mRNA expression of PGC-1α isoforms 1 and 4 (Figure 3C).”
Quote in the paperSubstantial claim - Findingown data
Apigenin increased phosphorylation of Akt in mouse quadricep muscle.
“Akt, a downstream effector of IGF and an upstream regulator of mTORC1, was observed to be phosphorylated in the presence of apigenin.”
Quote in the paperSubstantial claim - Findingown data
Apigenin increased quadricep muscle fiber size in male C57BL/6 mice.
“Results of hematoxylin and eosin (H&E) stains of quadricep cross-sections confirmed that apigenin increased muscle fiber size (Figure 1B-1C).”
- Also stated in: § Apigenin increases quadricep muscle weight and improves muscle function · plain
“Apigenin promoted quadricep muscle fiber hypertrophy.”
Quote in the paperSubstantial claim - Also stated in: § Apigenin increases quadricep muscle weight and improves muscle function · plain
- Findingown data
Apigenin increased mRNA expression of collagen III (Col3a1) in mouse quadricep muscle.
“Apigenin increased mRNA and protein expression of GPR56 and mRNA expression of its ligand, collagen III (Figure 3B and 3E).”
- Also stated in: § Apigenin upregulates mRNA expression of MHC and GPR56 signaling in mouse quadricep muscle and increases serum irisin levels · plain
“Apigenin increases GPR56 and Col3a1 mRNA expression.”
Quote in the paperSubstantial claim - Also stated in: § Apigenin upregulates mRNA expression of MHC and GPR56 signaling in mouse quadricep muscle and increases serum irisin levels · plain
- Findingown data
Among selected flavonoids, only apigenin significantly increased mRNA expression of MHC2A.
“We found that only apigenin significantly increased mRNA expression of MHC2A (Supplementary Figure S2).”
Quote in the paperSubstantial claim - Findingown data
Apigenin supplementation increases Prmt7 protein expression in mouse quadricep muscle.
“We observed that apigenin supplementation increases Prmt7 protein expression (Figure 3E).”
Quote in the paperSubstantial claim - Findingown data
Dietary apigenin increased quadricep muscle weight in a dose-dependent manner in male C57BL/6 mice fed apigenin-supplemented diet for 7 weeks.
“In the mice receiving apigenin, quadricep muscle weight increased in a dose-dependent manner (Figure 1A).”
- Also stated in: § Apigenin increases quadricep muscle weight and improves muscle function · plain
“Apigenin increased quadricep muscle weight in a dose-dependent manner.”
Quote in the paperSubstantial claim - Also stated in: § Apigenin increases quadricep muscle weight and improves muscle function · plain
- Findingown data
Dietary apigenin increased running distance on an accelerating treadmill in male C57BL/6 mice.
“Dietary apigenin also increased running distance on an accelerating treadmill (Figure 1D).”
- Also stated in: § Apigenin increases quadricep muscle weight and improves muscle function · plain
“Apigenin enhanced running distance on the accelerating treadmills.”
Quote in the paperNot a substantial claim - Also stated in: § Apigenin increases quadricep muscle weight and improves muscle function · plain
- Findingown data
Apigenin increased phospho-S6 in mouse quadricep muscle.
“Phospho-S6, a direct substrate of S6K1, was also increased by apigenin in mouse quadricep muscle (Figure 3E).”
Quote in the paperSubstantial claim - Interpretationown data
FNDC5 or irisin have minor effects on PGC-1α4 regulation of Prmt7.
“These results suggest that FNDC5 or irisin are minor effects on PGC-1α4 regulation of Prmt7.”
Quote in the paperSubstantial claim - Interpretationown data
Apigenin induces myogenic differentiation by regulating Prmt7-p38-myoD and the Akt-S6K1 pathway in C2C12 cells.
“We also found that apigenin induces myogenic differentiation by regulating Prmt7-p38-myoD and the Akt-S6K1 pathway in C2C12 cells.”
Quote in the paperSubstantial claim - Premisecitation
Prmt7 modulates PGC-1α expression via interaction with and activation of p38MAPK.
“Prmt7 modulates PGC-1α expression via interaction with and activation of p38MAPK [12].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [12] Kang, 2016, Prmt7 Deficiency Causes Reduced Skeletal Muscle Oxidative Metabolism and Age-Related Obesity, Diabetes source
Not checked in the free run.
- Interpretationown data
Prmt7 regulates FNDC5 expression.
“Our results show that knockdown of Prmt7 significantly reduces FNDC5 expression, whereas knockdown of FNDC5 does not appear to affect the expression of Prmt7.”
Quote in the paperSubstantial claim - Interpretationown data
The apigenin-induced increases in quadricep muscle weight and running distance in mice are attributable to upregulation of the Prmt7-PGC-1α-GPR56 signaling pathway.
“We found that apigenin increases quadricep muscle weight in mice and increases their running distance on an accelerating treadmill. These events are attributable to upregulation of the Prmt7-PGC-1α-GPR56 signaling pathway.”
Quote in the paperSubstantial claim- Rests on an assumption: The in vivo effects of apigenin on quadricep muscle weight and running distance are attributable to the Prmt7-PGC-1α-GPR56 pathway observed in C2C12 cells.
- Interpretationown data
Prmt7 regulates both PGC-1α1 and PGC-1α4 expression.
“We found in the present study that Prmt7 regulates both PGC-1α1 and PGC-1α4.”
Quote in the paperSubstantial claim - Premisecitation
Prmt7 is required for the maintenance of muscle stem cell regenerative capacity.
“Prmt7 is also required for the maintenance of muscle stem cell regenerative capacity [13].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [13] Richard, 2016, PRMT7 Preserves Satellite Cell Regenerative Capacity, Cell Reports source
Not checked in the free run.
- Study design and conductown data
Prmt7 protein expression was decreased by two different individual siPrmt7 sequences.
“We confirmed that Prmt7 protein expression was decreased by two different individual siPrmt7 sequences.”
Quote in the paperSubstantial claim - Interpretationown data
Apigenin improves muscle function in mice.
“Apigenin increases quadricep muscle weight and improves muscle function”
Quote in the paperSubstantial claim- Rests on an assumption: Running distance on an accelerating treadmill reflects skeletal muscle function in mice.
- The quote only partly states this claim. 1
- May combine two claims. 10
- Classified as probably not a substantial claim. 12
The quote only partly states this claim.
Findingown dataApigenin increased mRNA expression of MHC1, MHC2A, and MHC2B in quadricep muscle of male C57BL/6 mice in the Api-H group.
“We found that mRNA expression of MHC1, 2A, and 2B were significantly increased in the Api-H group (Figure 3A).”
- Also stated in: § Abstract · plain
“Apigenin stimulated mRNA expression of MHC (myosin heavy chain) 1, MHC2A, and MHC2B in the quadricep muscles of these animals.”
Quote in the paperSubstantial claim- Also stated in: § Abstract · plain
May combine two claims.
Findingown dataKnockdown of Prmt7 attenuates total PGC-1α, PGC-1α1, PGC-1α4, and GPR56 mRNA expression in C2C12 cells.
“The results showed that the knockdown of Prmt7 attenuates total PGC-1α, PGC-1α1, PGC-1α4, and GPR56 mRNA expression (Figure 5B-5E).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataApigenin did not significantly affect total body weight, heart, subcutaneous fat, epididymal fat, or liver weight in male C57BL/6 mice.
“However, apigenin did not significantly affect total body weight, heart, subcutaneous fat, epididymal fat, or liver weight (Figure 2A-2E).”
- Also stated in: § Apigenin increases quadricep muscle weight and improves muscle function · plain
“The weights of total body, heart, subcutaneous fat, epididymal fat, liver were not altered by apigenin supplementation.”
Quote in the paperNot a substantial claim- Also stated in: § Apigenin increases quadricep muscle weight and improves muscle function · plain
May combine two claims.
Findingown dataKnockdown of FNDC5 did not affect PGC-1α, PGC-1α4, or GPR56 expression, or phospho-Akt levels, although phospho-S6K1 and 4E-BP1 were attenuated.
“Moreover, knockdown of FNDC5 did not affect PGC-1α, PGC-1α4, or GPR56 expression, or phospho-Akt levels, although phopho-S6K1 and 4E-BP1 were attenuated (Supplementary Figure S5).”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationOverexpression of GPR56 increases IGF-1 expression via Gα12/13 and activates mTORC1, resulting in muscle hypertrophy.
“Overexpression of GPR56 increases IGF-1 expression via Gα12/13 and activates mTORC1, which results in muscle hypertrophy [15].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [15] Spiegelman, 2014, G protein-coupled receptor 56 regulates mechanical overload-induced muscle hypertrophy, Proc Natl Acad Sci USA source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationApigenin prevents LPS-induced atrogin-1 expression in C2C12 myotubes by regulating phosphorylation of JNK.
“It was previously shown that apigenin prevents LPS-induced atrogin-1 expression in C2C12 myotubes by regulating phosphorylation of JNK [24].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [24] Nikawa, 2015, Flavones Inhibit LPS-Induced Atrogin-1/MAFbx Expression in Mouse C2C12 Skeletal Myotubes, J Nutr Sci Vitaminol (Tokyo) source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationBoth IGF1 and IGF2 regulate skeletal muscle development and adult muscle regeneration and hypertrophy.
“Both IGF1 and IGF2 regulate skeletal muscle development and adult muscle regeneration and hypertrophy [10]”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [10] Chen, 2008, PLD regulates myoblast differentiation through the mTOR-IGF2 pathway, J Cell Sci source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationMyoD activity is regulated by promyogenic signaling pathways including p38 MAPK and Akt.
“The activity of MyoD is regulated by promyogenic signaling pathways which include p38 mitogen-activated protein kinase (p38 MAPK) and Akt [5, 7, 8].”
Quote in the paperNot a substantial claim0 of 3 sources checked- cites [5] Bae, 2014, Tetrahydropalmatine promotes myoblast differentiation through activation of p38MAPK and MyoD, Biochem Biophys Res Commun source
Not checked in the free run.
- cites [7] Bengal, 1999, p38 mitogen-activated protein kinase pathway promotes skeletal muscle differentiation. Participation of the Mef2c transcription factor, J Biol Chem source
Not checked in the free run.
- cites [8] Rotwein, 2007, Selective control of skeletal muscle differentiation by Akt1, J Biol Chem source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationAkt and mTORC1, downstream effectors of IGF1, are critical regulators of skeletal muscle hypertrophy.
“while Akt and mTORC1, downstream effectors of IGF1, are critical regulators of skeletal muscle hypertrophy [11].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [11] Yancopoulos, 2001, Akt/mTOR pathway is a crucial regulator of skeletal muscle hypertrophy and can prevent muscle atrophy in vivo, Nat Cell Biol source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationMyoD initiates differentiation to the skeletal muscle lineage and the formation of myoblasts.
“MyoD (Myoblast determination protein) initiates differentiation to the skeletal muscle lineage and the formation of myoblasts [6].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [6] Rudnicki, 2012, Building muscle: molecular regulation of myogenesis, Cold Spring Harb Perspect Biol
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationGPR56 is a transcriptional target of PGC-1α4 and is induced by resistance exercise.
“The G protein-coupled receptor 56 (GPR56) is a transcriptional target of PGC-1α4 and is induced by resistance exercise [15].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [15] Spiegelman, 2014, G protein-coupled receptor 56 regulates mechanical overload-induced muscle hypertrophy, Proc Natl Acad Sci USA source
Not checked in the free run.
May combine two claims.
Interpretationown dataApigenin increases skeletal muscle hypertrophy and myogenic differentiation.
“In the present study, we found that apigenin increases skeletal muscle hypertrophy and myogenic differentiation.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationPGC-1α4 is highly expressed in exercising skeletal muscle, increases IGF1 expression, and induces skeletal muscle hypertrophy.
“PGC-1α4 has been found to be highly expressed in exercising skeletal muscle, which increases IGF1 expression, and induces skeletal muscle hypertrophy [14].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [14] Okutsu, 2012, A PGC-1α isoform induced by resistance training regulates skeletal muscle hypertrophy, Cell source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationThe C2C12 myoblast line is a well-established model for the study of myogenic differentiation.
“The C2C12 myoblast line is a well-established model for the study of myogenic differentiation [25].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [25] Li, 2015, Molecular Basis for the Regulation of Transcriptional Coactivator p300 in Myogenic Differentiation, Sci Rep source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Study design and conductown dataFour different siRNAs were tested for knockdown effectiveness, and two siRNAs were selected.
“Four different siRNAs were tested for knockdown effectiveness, and two siRNAs were selected.”
Quote in the paperNot a substantial claimMay combine two claims.
Interpretationown dataApigenin may have the potential to prevent inactivity-induced atrophy and age-related sarcopenia.
“We observed that apigenin promotes increased expression of MHC1, MHC2A and MHC2B, implying that apigenin may have the potential to prevent inactivity-induced atrophy and age-related sarcopenia.”
Quote in the paperSubstantial claim- Rests on an assumption: The effects of apigenin on young male C57BL/6 mouse quadricep muscle and C2C12 cells are predictive of effects on aged human skeletal muscle and sarcopenia.
Probably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenAll animal experiments were performed according to procedures approved by the Institutional Animal Care and Use Committee of the Korea Food Research Institute.
“All animal experiments were performed according to procedures approved by the Institutional Animal Care and Use Committee of the Korea Food Research Institute (KFRI-IACUC, #2016-0011).”
Quote in the paperNot a substantial claimClassified as probably not a substantial claim. May combine two claims.
PremisecitationKnockdown of Prmt7 reduces MHC and myogenin expression, as well as p38 phosphorylation.
“A previous study has shown that knockdown of Prmt7 reduces MHC and myogenin expression, as well as p38 phosphorylation [12].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [12] Kang, 2016, Prmt7 Deficiency Causes Reduced Skeletal Muscle Oxidative Metabolism and Age-Related Obesity, Diabetes source
Not checked in the free run.
The paper relies on this without support.
The effects of apigenin on young male C57BL/6 mouse quadricep muscle and C2C12 cells are predictive of effects on aged human skeletal muscle and sarcopenia.
“These results suggest that apigenin could be used as a functional food to prevent muscle loss and enhance muscle function.”
The paper relies on this without support.
The in vivo effects of apigenin on quadricep muscle weight and running distance are attributable to the Prmt7-PGC-1α-GPR56 pathway observed in C2C12 cells.
“These events are attributable to upregulation of the Prmt7-PGC-1α-GPR56 signaling pathway.”
The paper relies on this without support.
Running distance on an accelerating treadmill reflects skeletal muscle function in mice.
“Apigenin increases quadricep muscle weight and improves muscle function”
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TEAD is a potential anabolic agent containing 20-HE together with other secondary metabolites previously reported to have anabolic effects and activities that promote muscle health.
“It could be concluded that TEAD is a potential anabolic agent containing 20-HE together with other secondary metabolites which previously reported to have anabolic effects and activities that promote muscle health [7,73,74,75,76,77,78].”
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Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
Nucleus-ratio numerator is defined two different ways
MinorThe results define the numerator as the number of MHC-positive multinucleated cells, whereas the Figure 4 caption defines it as the number of nuclei within those cells. Those are different counts.
“The nuclear ratio is defined as the number of MHC-positive multinucleated cells divided by the total number of nuclei in a cell population.”
“Nucleus ratio was calculated as the average number of nuclei in MHC positive multinucleated cells above total nuclei.”
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Atrogin-1, a muscle-specific F-box protein highly expressed during muscle atrophy
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Building Muscle: Molecular Regulation of MyogenesisPreprint
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Association between muscular strength and mortality in men: prospective cohort study
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- Authors
- Jang, Y. J., Son, H. J., Choi, Y. M., Ahn, J., Jung, C. H., & Ha, T. Y.
- Affiliations
- Korea Food Research Institute (KR)
- Corresponding author
- Jang, Young Jin
- Son, Hyo Jeong
- Venue
- Oncotarget
- Publisher
- Impact Journals, LLC
- Published
- 2017-09-16
- Volume
- 8
- Issue
- 45
- Pages
- 78300-78311
- ISSN
- 1949-2553 (ISSN-L)
- PMC
- PMC5667963
- OpenAlex
- W2754104367
- Cited by
- 59
- References
- 41
- Citations by year
- 2026: 3 · 2025: 8 · 2024: 7 · 2023: 9 · 2022: 6 · 2021: 8 · 2020: 8 · 2019: 2 · 2018: 7
- FWCI
- 1.90
- Type
- journal article
- Language
- en
- Open access
- diamond
- doi.org
- Licence
- cc-by
- Locations
- Oncotarget (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- Korea Food Research Institute (E0160500, E0160500‐02)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Muscle Physiology and Disorders
- Health Sciences › Medicine › Pharmacology › Flavonoids in Medical Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Muscle metabolism and nutrition
- Keywords
- PRMT7, skeletal muscle hypertrophy, myogenesis, GPR56, type III collagen, PGC-1α, mTORC1, Akt signaling, irisin, FNDC5, myosin heavy chain isoforms, MyoD, p38 MAPK, C2C12 myoblasts, flavonoids
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.
Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-10.
Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-10.
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 ›
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