16 replies to this topic

[kenj]

Few weeks ago, I found myself ending up with an aching left ankle from everyday morning runs, following a resv upgrade (going from, IIRC, 3-600mg to 1.1G, - 99% extract).
I ran through the mega 500 club thread, and noted a few posters mentioning trouble with achilles (tendinitis), possibly related to resv supplementation.
So, - the pain from my ankle in motion might be due to overstraining it, and NOT related to resv by at all, but I've been running/day for many years, with the latest 18 months in great form, and this sudden pain did occur after riding the resv wagon...

Re: quercetin, I wasn't taking it with resveratrol, however I did get ~150mg of quercetin dihydrate from other sups; - if it were to influence resv uptake in humans, and possibly provoke tendinitis, I wonder what dose makes the poison (in susceptible individuals)? We do get quercetin from the diet also.
Do we have any other experiences with people exercising (distance runners) taking high-dose resv with quercetin?

[Matt]

At the time I was taking resveratrol I had tendinitis after doing long runs, and it lasted ages before it got better. Quite painful! It was exactly where that diagram shows that red spot. Although I'm also doing CR so I might be a little more prone to injury.

[lucid]

Stretching those bad boys out may help you a bunch. I find stretching odd parts of my body like my feet to be very important when returning from an inactive period. I run about twice a week, and have noticed a decrease in any pain I feel or soreness if anything at all. I have been on 2g Resv / day for about 1 month, and .5g / day for the 2 months before that.

[scottl]

If tendinitis is still an issue look up ART i.e. active release technique. You can find people's experiences on the mind and muscle forum and the bodyrecomposition forum. near magic for soft tissue injuries.

[krillin]

If it is caused by resveratrol decreasing angiogenesis, then you'd have to back off of hordes of other phytochemicals too.

Topical MSM is the best thing I've found for tendon problems.

[kenj]

Thx for your replies. Well, I'm ready to take up aerobic exercise again following a 2 week break. I'll cut quercetin, and pause resv for a week or so.

[krillin]

Here are some references to back up my statement.

Ann N Y Acad Sci. 1999 Jun 30;878:228-35.
Preclinical and clinical studies of MMP inhibitors in cancer.
Drummond AH, Beckett P, Brown PD, Bone EA, Davidson AH, Galloway WA, Gearing AJ, Huxley P, Laber D, McCourt M, Whittaker M, Wood LM, Wright A.
British Biotech Pharmaceuticals Limited, Oxford, United Kingdom. drummond@britbio.co.uk

The role of matrix metalloproteinases in tumor angiogenesis and growth is now well recognized for models of both human and animal cancer. Clinical studies currently under way with the prototype matrix metalloproteinase inhibitor, marimastat, will establish whether inhibitors of these enzymes are of benefit in the treatment of different types of human cancer. On chronic therapy in humans, marimastat induces a reversible tendinitis that can also be detected in certain animal species. This paper compares the ability of broad-spectrum and various types of selective matrix metalloproteinase inhibitors to induce tendinitis and to exhibit anticancer effects in an animal cancer model. Under conditions in which both systemic exposure and inhibitor potency are controlled, selective inhibitors are less pro-tendinitic, but are weaker anticancer agents than broad-spectrum agents such as marimastat. The clinical relevance of these findings is discussed.

PMID: 10415734

J Nutr Biochem. 2007 Jul 23;
Resveratrol inhibits heregulin-beta1-mediated matrix metalloproteinase-9 expression and cell invasion in human breast cancer cells.
Tang FY, Chiang EP, Sun YC.
Biomedical Science Laboratory, Department of Nutrition, China Medical University, Taichung 40402, Taiwan, ROC.

The growth factor heregulin-beta1 (HRG-beta1), which is expressed in breast cancer, activates the HER-2 signaling pathway through induction of heterodimeric complexes of HER-2 with HER-3 or HER-4. It has been shown in many studies that HRG-beta1 induces the tumorigenicity and metastasis of breast cancer cells. Matrix metalloproteinase (MMP) 9 is a key enzyme in the degradation of extracellular matrices, and its expression may be dysregulated in breast cancer invasion and metastasis. Resveratrol, a major component in grape, exhibited potential anticarcinogenic activities in both in vitro and in vivo studies. However, the inhibitory effect of resveratrol on HER-2-mediated expression of MMP-9 has not been demonstrated yet. In the present study, we investigated the anti-invasive mechanism of resveratrol in human breast cancer cells. Human breast cancer MCF-7 cells were exposed to resveratrol (2, 5 and 10 muM). The expression activity of MMP-9 was measured by zymogram analysis. Phosphorylated levels of HER-2 and mitogen-activated protein kinase (MAPK)/ERK were measured by Western blot analysis. Total actin was used as internal control for protein expression. HRG-beta1 induced the phosphorylation of HER-2/neu receptor and MMP-9 expression in human breast cancer MCF-7 cells. Resveratrol significantly inhibited HRG-beta1-mediated MMP-9 expression in human breast cancer cells. MEK inhibitor induced a marked reduction in MMP-9 expression, and it suggested that ERK1/2 cascade could play an important role in HRG-beta1-mediated MMP-9 expression. Furthermore, resveratrol significantly suppressed HRG-beta1-mediated phosphorylation of ERK1/2 and invasion of breast cancer cells. However, resveratrol had negligible effects on either HRG-beta1-mediated phosphorylation of HER-2 receptor or expression of the tissue inhibitor of MMP, tissue inhibitor metalloproteinase protein 1. Taken together, our results suggest that resveratrol inhibited MMP-9 expression in human breast cancer cells. The inhibitory effects of resveratrol on MMP-9 expression and invasion of breast cancer cells are, in part, associated with the down-regulation of the MAPK/ERK signaling pathway.

PMID: 17651959

[niner]

Thanks for those refs, Krillin. Apparently MMPs are involved in tendon health. It sounds like there must be some sort of remodeling going on there. The J. Nutr. Biochem. paper is an in vitro study where the bottom of the resveratrol concentration profile was 2 uM, a level that most of us probably are not seeing. I'll cross my fingers and hope that resveratrol is only a weak MMP9 suppressor, or that it's specific to that MMP, or something. This is of interest to me (and most of us, I'd guess) as I'm physically active and battle tendon and ligament issues. (All of which occurred before I was using high doses of rsv.) On the other hand, if I ever get cancer I'll probably be happy to have an MMP9 suppressor on board, but at the moment it seems like an activity that I'd rather not have.

[dannov]

What of the Quercetin? It acts as a SIRT1 inhibitor, the opposite of Res.

[krillin]

OK people, line up to spank me. I was 180 degrees off on this one. The broad-spectrum MMP-inhibiting drugs cause tendinitis by taking out sheddases in addition to MMPs. MMPs appear to be bad for tendons.

Matrix Metalloproteinases: Pro- and Anti-Angiogenic Activities

Controlling for systemic dose and inhibitor potency, the MMP-selective (collagense-, gelatinase-) inhibitors caused less tendinitis but were also less effective as anticancer agents. Interestingly, at equivalent dosages, one of the broad spectrum MMPI tested that had less ability to inhibit certain MMP-like enzymes known as membrane protein ''sheddases'' also exhibited less capability to induce tendinitis. ''Sheddases'' are metalloenzymes that release membrane-associated proteins, some of which are growth factors and cytokines such as transforming growth factor (TGF-alpha) (Arribas et al. 1996) and tumor necrosis factor (TNF-alpha), and have previously been shown to be inhibited by certain MMPI (Gearing et al. 1994).

J Cell Biochem. 2005 Sep 1;96(1):117-25.
Mechanical loading stimulates ecto-ATPase activity in human tendon cells.
Tsuzaki M, Bynum D, Almekinders L, Faber J, Banes AJ.
Department of Orthopaedics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-7055, USA. Mari_tsuzaki@med.unc.edu

Response to external stimuli such as mechanical signals is critical for normal function of cells, especially when subjected to repetitive motion. Tenocytes receive mechanical stimuli from the load-bearing matrix as tension, compression, and shear stress during tendon gliding. Overloading a tendon by high strain, shear, or repetitive motion can cause matrix damage. Injury may induce cytokine expression, matrix metalloproteinase (MMP) expression and activation resulting in loss of biomechanical properties. These changes may result in tendinosis or tendinopathy. Alternatively, an immediate effector molecule may exist that acts in a signal-dampening pathway. Adenosine 5'-triphosphate (ATP) is a candidate signal blocker of mechanical stimuli. ATP suppresses load-inducible inflammatory genes in human tendon cells in vitro. ATP and other extracellular nucleotide signaling are regulated efficiently by two distinct mechanisms: purinoceptors via specific receptor-ligand binding and ecto-nucleotidases via the hydrolysis of specific nucleotide substrates. ATP is released from tendon cells by mechanical loading or by uridine 5'-triphosphate (UTP) stimulation. We hypothesized that mechanical loading might stimulate ecto-ATPase activity. Human tendon cells of surface epitenon (TSC) and internal compartment (TIF) were cyclically stretched (1 Hz, 0.035 strain, 2 h) with or without ATP. Aliquots of the supernatant fluids were collected at various time points, and ATP concentration (ATP) was determined by a luciferin-luciferase bioluminescence assay. Total RNA was isolated from TSC and TIF (three patients) and mRNA expression for ecto-nucleotidase was analyzed by RT-PCR. Human tendon cells secreted ATP in vitro (0.5-1 nM). Exogenous ATP was hydrolyzed within minutes. Mechanical load stimulated ATPase activity. ATP was hydrolyzed in mechanically loaded cultures at a significantly greater rate compared to no load controls. Tenocytes (TSC and TIF) expressed ecto-nucleotidase mRNA (ENTPD3 and ENPP1, ENPP2). These data suggest that motion may release ATP from tendon cells in vivo, where ecto-ATPase may also be activated to hydrolyze ATP quickly. Ecto-ATPase may act as a co-modulator in ATP load-signal modulation by regulating the half-life of extracellular purine nucleotides. The extracellular ATP/ATPase system may be important for tendon homeostasis by protecting tendon cells from responding to excessive load signals and activating injurious pathways.

PMID: 16052485

[krillin]

I'll cross my fingers and hope that resveratrol is only a weak MMP9 suppressor, or that it's specific to that MMP, or something.

Correct-o-mundo. Resveratrol inhibits only MMP-9. Other phytochemicals aren't so selective.

[krillin]

Resveratrol is a COX inhibitor, and they increase MMPs. Maybe that's how resveratrol might be causing tendon problems.

Clin Pharmacol Ther. 2006 Apr;79(4):303-15.
Rofecoxib regulates the expression of genes related to the matrix metalloproteinase pathway in humans: implication for the adverse effects of cyclooxygenase-2 inhibitors.
Wang XM, Wu TX, Lee YS, Dionne RA.
Pain and Neurosensory Mechanisms Branch and Biostatistics Core, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20892, USA.

BACKGROUND: Cyclooxygenase-2 (COX-2) and COX-2-derived prostaglandins contribute to acute inflammation and pain, as well as resolution of inflammation; inhibition of COX-2 results in persistence of inflammation. Because matrix metalloproteinases (MMPs) play an essential role in inflammatory tissue injury and their activity is regulated by COX-2-derived prostaglandin E2, we evaluated whether COX-2 inhibition is associated with MMP overexpression during acute inflammation. METHODS: A total of 102 oral mucosal biopsy specimens were taken from 51 healthy volunteers who required extraction of impacted third molars. Subjects randomly received either rofecoxib (50 mg daily), ibuprofen (400 mg 4 times per day), or placebo 90 minutes before surgery and up to 48 hours after surgery. Total ribonucleic acid extracted from each biopsy specimen was used to analyze changes in gene expression related to the MMP pathway after tissue injury and drug treatments by use of microarray and quantitative real-time polymerase chain reaction in this clinical model of acute inflammation. RESULTS: Following tissue injury, rofecoxib increased the expression of genes associated with degradation of the extracellular matrix, including MMP-1 (64.7 +/- 6.5, P = .010), MMP-3 (41.7 +/- 4.8, P = .007), PLAT (encoding tissue plasminogen activator) (10.9 +/- 4.6, P = .032), and IL8 (encoding interleukin 8) (8.3 +/- 6.7, P = .020), and decreased the expression of TIMP3 (encoding tissue inhibitor of metalloproteinase 3) (6.2 +/- 2.8, P = .027). Ibuprofen produced similar effects on the expression of MMP-1 (23.4 +/- 5.0, P = .016) and MMP-3 (26.3 +/- 4.2, P = .003). In contrast, the expression of these genes was not statistically changed after tissue injury in the placebo group. The microarray data were in concordance with the changes in gene expression confirmed by quantitative real-time polymerase chain reaction. CONCLUSION: These findings provide evidence at the transcriptional level that inhibition of COX-2, in the presence of acute inflammation, induces changes in gene expression related to the MMP pathway. These changes may contribute to the adverse effects attributed to COX-2 inhibition by interfering with resolution of inflammation.

PMID: 16580899

[krillin]

Some mechanistic details. If you're going to inhibit COX, you'd better inhibit ERK too. Which resveratrol does... (see above) I am thus unable to come up with any mechanism for resveratrol contributing to tendinitis, unless the extra energy is making people ramp up their activity.

J Immunol. 2003 Dec 1;171(11):6080-9.
Cyclooxygenase-2-derived E prostaglandins down-regulate matrix metalloproteinase-1 expression in fibroblast-like synoviocytes via inhibition of extracellular signal-regulated kinase activation.
Pillinger MH, Rosenthal PB, Tolani SN, Apsel B, Dinsell V, Greenberg J, Chan ES, Gomez PF, Abramson SB.
Division of Rheumatology, Department of Medicine, New York University School of Medicine, New York, NY 10016, USA. michael.pillinger@med.nyu.edu

We examined the regulation of matrix metalloproteinase (MMP) production by mitogen-activated protein kinases and cyclooxygenases (COXs) in fibroblast-like synoviocytes (FLSCs). IL-1beta and TNF-alpha stimulated FLSC extracellular signal-regulated kinase (ERK) activation as well as MMP-1 and -13 release. Pharmacologic inhibitors of ERK inhibited MMP-1, but not MMP-13 expression. Whereas millimolar salicylates inhibited both ERK and MMP-1, nonsalicylate COX and selective COX-2 inhibitors enhanced stimulated MMP-1 release. Addition of exogenous PGE(1) or PGE(2) inhibited MMP-1, reversed the effects of COX inhibitors, and inhibited ERK activation, suggesting that COX-2 activity tonically inhibits MMP-1 production via ERK inhibition by E PGs. Exposure of FLSCs to nonselective COX and selective COX-2 inhibitors in the absence of stimulation resulted in up-regulation of MMP-1 expression in an ERK-dependent manner. Moreover, COX inhibition sufficient to reduce PGE levels increased ERK activity. Our data indicate that: 1) ERK activation mediates MMP-1 but not MMP-13 release from FLSCs, 2) COX-2-derived E PGs inhibit MMP-1 release from FLSCs via inhibition of ERK, and 3) COX inhibitors, by attenuating PGE inhibition of ERK, enhance the release of MMP-1 by FLSC.

PMID: 14634122

[krillin]

What of the Quercetin?  It acts as a SIRT1 inhibitor, the opposite of Res.

Quercetin and the glucuronide are good ERK-wise, while the sulphate is bad. The glucuronide is a SIRT1 inhibitor, so it would be be bad NF-kB-wise.

Br J Nutr. 2006 May;95(5):1016-23.
Divergent effects of quercetin conjugates on angiogenesis.
Donnini S, Finetti F, Lusini L, Morbidelli L, Cheynier V, Barron D, Williamson G, Waltenberger J, Ziche M.

Section of Pharmacology, Department of Molecular Medicine, University of Siena, Via A. Moro 2, 53100 Siena, Italy.

The present study reports the activities of quercetin and its main circulating conjugates in man (quercetin-3'-sulphate (Q3'S) and quercetin-3-glucuronide (Q3G)) on in vivo angiogenesis induced by vascular endothelial growth factor (VEGF) and examines the effects of these molecules on cultured endothelial cells. We found opposing effects of quercetin and its metabolites on angiogenesis. While quercetin and Q3G inhibited VEGF-induced endothelial cell functions and angiogenesis, Q3'S per se promoted endothelial cell proliferation and angiogenesis. The inhibitory effect elicited by Q3G was linked to inhibition of extracellular signal-regulated kinases 1/2 (ERK1/2) phosphorylation elicited by VEGF. The activation of endothelial cells by Q3'S was associated to stimulation of VEGF receptor-2 and to downstream signalling activation (phosphatidylinositol-3 kinase/Akt and nitric oxide synthase pathways), ultimately responsible for ERK1/2 phosphorylation. These data indicate that the effects of circulating quercetin conjugates on angiogenesis are different depending on the nature of the conjugate. Q3G and Q3'S are the two major conjugates in plasma, but their ratio is dependent on several factors, so that inhibition or activation of angiogenesis could be subtly shifted as a result of metabolism in vivo.

PMID: 16611395

[stephen_b]

This may be a totally off-the-wall observation, but it seems to me that I am getting better swimming performance due to flexibility increases with resveratrol. In particular, my kick when doing the crawl seems to have gained more "traction" than it ever has before. I've been a semi-competent swimmer, but the propulsion I get from my kick is more now than I remember it ever being. Anyway, take with a tablespoon of salt.

Stephen

[krillin]

Low-dose quercetin didn't affect MMP-2, but it did lower TIMP-1.

Mutat Res. 2001 Sep 1;480-481:269-76.
Dietary supplementation with the anti-tumour promoter quercetin: its effects on matrix metalloproteinase gene regulation.
Morrow DM, Fitzsimmons PE, Chopra M, McGlynn H.
Cancer and Ageing Research Group, School of Biomedical Sciences, University of Ulster at Coleraine, Coleraine BT52 1SA, Northern Ireland, UK.

Dietary modification, especially the consumption of larger amounts of fruits and vegetables can act to decrease the risk of a variety of human cancers. Quercetin, a bioflavonoid widely distributed in fruits and vegetables has been shown to have a chemoprotective role in cancer, through complex effects on signal transduction involved in cell proliferation and angiogenesis. In this study we examined the effects of dietary supplementation of quercetin (30 mg per day) incorporated into a black currant drink. Healthy male subjects aged between 33 and 64 years (mean=47.1 years) received either quercetin or placebo for 14 days. Blood samples were taken at baseline and upon completion of the study and analysed for full blood count, matrix metalloproteinase-2 (MMP-2), tissue inhibitor of matrix metalloproteinse-1 and -2 (TIMP-1 and -2) plasma levels using ELISA techniques. RNA was extracted from the peripheral blood lymphocytes and reverse transcriptase-polymerase chain reaction (RT-PCR) carried out for MMP-2 and TIMP-1, TIMP-2 gene expression determination. Supplementation of the diet with quercetin did not alter the MMP-2 or TIMP-2 gene transcription or plasma protein levels of the healthy subjects in this study. The TIMP-1 gene transcription and plasma protein levels (311+/-70 ng/ml at baseline to 183+/-35 ng/ml post-supplementation, P<0.05) of the subjects in this study were, however, significantly decreased following quercetin supplementation. This is an interesting result, as there is some controversy over the functions of TIMP-1 in tumour progression. In certain model systems, artificially increased TIMP-1 levels prevent or decrease tumour growth. However, in other studies high levels of TIMP-1 have been correlated with aggressive disease and poor prognosis in patients with certain malignancies. This study has outlined a potential role for the anti-tumour promoter quercetin as a dietary mediator of the carcinogenic cascade.

PMID: 11506819

[niner]

Wow. 30mg/d of quercetin cut TIMP-1 almost in half. What would happen if you took 500mg? "[A] potential role for the anti-tumour promoter quercetin as a dietary mediator of the carcinogenic cascade." Hmm. Problem is, we don't know what direction it mediates in... Suppressing endogenous protease inhibitors sounds like a route to trouble, though. At least quercetin is available in a healthy diet at pretty decent levels, so low doses are probably safe.