KGK Synergize “In addition to the possible analgesic effects facilitated by NMDA receptor inhibition, both copper and nicotinic acid are thought to support mitochondrial function by improving cellular respiration, thus increasing ATP production (1-3). Studies investigating muscle pain in relation to occupational work have demonstrated that sore muscle displays changes in structure indicating mitochondrial disturbances and reduced oxygenation (4,5). A recent study found that nicotinic acid treatment improved overall cellular respiration and was able to reverse deleterious effects on crucial cellular functions that are impaired in mitochondrial respiratory chain diseases (2). Copper is required within the mitochondria for assembly of the enzymes cytochrome c oxidase (CcO) and superoxide dismutase (Sod1). Decreased rates of electron transfer observed in dysfunctional mitochondria are most often due to diminished activity of CcO (6). Reports have shown that supplementation of copper can reverse CcO deficiency, thus increasing production of ATP (1,7,8). The enhancement of mitochondrial function by copper and nicotinic acid may also act to prevent the structural changes in muscle that are associated with pain.
Both copper and nicotinic acid on their own are essential for many biological processes and have been used as therapeutic agents. Copper is necessary for the activity of several key enzymes in the cell, primarily in the mitochondria where it plays a role in energy metabolism and protection against oxidative stress (1,9,10). Copper complexes can also modulate copper homeostasis in the brain, resulting in protective effects in several models of neurodegeneration (9). Copper is also important in synaptic function, specifically regarding axonal targeting and synaptogenesis (10,12).
Nicotinic acid, also known as niacin or vitamin B3, plays a role in production of energy, signal transduction, regulation of gene expression, and is involved in the synthetic pathway of lipids (13,15). It has long been used as broad-spectrum lipid drug, as it lowers the levels of all atherogenic lipoproteins and raises the levels of the protective HDL lipoproteins (13). Recently, nicotinic acid has been shown to partially restore normal functioning in cells taken from patients with mitochondrial diseases by normalizing signaling activity and improving overall cellular respiration(2). “
BDLbiochem …. KGK did a very impressive job of summarizing the peer reviewed literature. The participates with neuro muscular pain that they were able to recruit added a new out look opened new possibilities. One thing that caught my attention was the large number of participants in the study that had neck and shoulder discomfort. Trapezius muscle discomfort is very common among office workers. Another thing that caught my attention was that many of the participants started the study dehydrated. Dehydration can lead to release of angiotensin II. Angiotensin II not only causes blood vessels to contract but also activates NADPH oxidase to produce a reactive oxygen species superoxide. As a general background (8),
- Acetylcholine binds to receptors on the membranes of endothelial cells.
- Activated phospholipase C cleaves IP3 from its parent phospholipid.
- IP3 causes the release of Ca2+ from intracellular stores.
- Ca2+ binds to calmodulin.
- Ca2+CaM activates nitric oxide synthase, which produces nitric oxide.
- Nitric oxide binds to guanylate cyclase in smooth muscle of blood vessels.
- Guanylate cyclase converts GTP to cyclic GMP.
- cGMP activates protein kinase G.
- Protein kinase G phosphorylates proteins that cause smooth muscle to relax.
If superoxide (O2.-) is present, from neutrophils from the innate immune system, also produces O2.- which reacts with nitric oxide (NO) to form peroxynitrite (ONOO–) before NO. can cause blood vessels to dilate.
Dietary Copper matters
Cu/Zn is important
Dietary copper influences acetylcholine induced vasorelaxation in the rat (17). , Arteriole dilation in response to increasing concentrations of acetylcholine (10-7 to 10-4 ) was measured in vivo in the cremaster muscle microcirculation for each dietary copper group:
Schuschke and coworkers (17) used liver copper concentration and aortic and erythrocyte Cu/Zn-SOD activity as indices of systemic copper status. When Cu increased from 0 μg per gram dry weight in the liver an exponential increase in 10-5 M acetylcholine (Ach) induced vasodilation was seen. This suggested that concentrations below 5 μg copper per dry liver weight results in attenuated vasodilation.
Copper deficiency prevents vasodilation
An earlier study from the same group, using a similar model (18), suggested that Cu/Zn SOD3 protected nitric oxide’s role as a vasodilator by scavenging superoxide before it could react with nitric oxide. Cremaster arteriole endothelial intracellular Ca2+ stimulated by 10-6 M Ach was significantly inhibited in the arterioles from Cu deficient rats. The inhibition of Ca2+ and vasodilation was accompanied by a depression of vascular Cu/Zn-SOD activity and an increase in plasma peroxynitrite activity. The authors suggested oxidative damage to proteins involved in Ca2+ signaling (18).
Copper protects NO
Another study from the Schuschke group (19) compared nitric oxide production from lung microvascular endothelial cells made copper deficient with a chelator with copper adequate endothelial cells. A fluorescent NO indicator showed NO significantly decreased in the copper deficient endothelial cells under basal as well as acetylcholine stimulated conditions (19). This group found he same thing in the cremator muscle arterioles from the copper deficient versus copper sufficient rats (19). They used kidney and liver concentrations of copper to verify deficiency. Blood plasma not considered a reliable indicator of copper status.
A different group examined the relationship between angiotensin II induced superoxide production increases in blood pressure and its mitigation by Menke’s (MNK, aka ATP7A) copper transporter (Qin 2008).
It’s also about copper (+1) loading
A different group examined the relationship between angiotensin II induced superoxide production increases in blood pressure and its mitigation by Menke’s (MNK, aka ATP7A) copper transporter (20).
In the model developed in this study Angiotensin II causes the extracellular SOD3 to associate with ATP7A (MNK) in the Golgi for Cu loading before it is secreted (Qin 2008). The end result is that superoxide is scavenged before it can react with NO. The blood work suggested that patients in the Mitosynergy/KGK Synergize study might have started out with high angiotensin II, an activator of NADPH oxidase that produces superoxide.
Are changes in muscle microcirculation involved in chronic muscle discomfort?
Many of the participants in the KGK study had chronic shoulder pain, presumably in the trapezius. This is a common site of pain for those who spend a lot of time at the key board. The following is a brief review of the literature involving vascular changes in trapezius muscle pain. This image was compiled for the reader to conceptualize the trapezius muscle discomfort from repetitive key boarding.
- Right handed female office workers, with and without chronic pain in the trapezius muscle, were asked to perform tasks such as typing and mousing. The main finding of this study was that 1 h of combined workstation tasks resulted in decreased oxygen saturation and blood flow in the upper, middle, and lower trapezius (21). Oxygen saturation was significantly lower in the trapezius myalgia cases compared to the control group (p = 0.027). Blood flow of the upper trapezius on the right side was significantly lower than the blood flow on the left side (p = 0.026).
- Blood flow in female and male patients diagnosed with trapezius myalgia were compared with healthy controls. The right and left trapezius muscles of all individuals were examined simultaneously with laser-Doppler flowmetry (LDF) and surface EMG during a fatiguing series of step-wise-increased contractions. Duration was for 1 min with 1 min rest in between. (22). Trapezius myalgia patients showed significantly lower blood flow in the painful side with low contraction frequencies.
- Another office worker trapezius myalgia study showed pain in the active side correlated positively with blood flux in the pain-afflicted subjects and negatively in the reference group. This study showed that pain is associated with trapezius vasodilation but not with muscle activity (23). This study came to the conclusion that interaction between blood vessels and nociceptors may be important in the activation of muscle nociceptors in people with chronic shoulder and neck pain (23).
- Metabolic substances and trapezius blood flow were measured in female office workers with and without chronic pain over the course of an eight hour day (Larsson 2008). Increased concentrations of glutamate and pyruvate were seen in the pain group compared to the controls. Increased blood flow was seen in the trapezius pain group (24).
- Office workers with trapezius myalgia were compared with pain free office workers performing repetitive “peg board” and a stress task. Insufficient muscle blood flow and oxygenation were proposed to account for the higher lactate, pyruvate and pain responses among myalgia suffers versus controls (25).
- A study sought to compare blood flow and oxygen saturation with trapezius and extensor carpi radius muscle fatigue in workers with and without work related muscle pain (26). While fatigue in response to repetitive tasks occurred earlier in the pain group, no changes were seen in hemodynamics and blood oxygen saturation between the control and he pain group (26). These authors that a central, rather than a peripheral, mechanism accounted for the early fatigue.
Much information exists on the role of nitric oxide, blood flow, and discomfort in muscle groups that do not receive adequate blood flow. The role of copper supplements in mitigating muscle discomfort due to inadequate blood flow deserves follow up in a better controlled study. See study results for tasks that became less uncomfortable with the group on Cu(I)NA2.
- Salviati L, Hernandez-Rosa E, Walker WF et al. Copper supplementation restores cytochrome c oxidase activity in cultured cells from patients with SCO2 mutations. Biochem J 2002;363:321-7.
- Zhang Z, Tsukikawa M, Peng M et al. Primary respiratory chain disease causes tissue-specific dysregulation of the global transcriptome and nutrient-sensing signaling network. PLoS One 2013;8:e69282.
- DiMauro S, Schon EA. Mitochondrial respiratory-chain diseases. N Engl J Med 2003;348:2656-68.
- Gracely RH, Petzke F, Wolf JM, Clauw DJ. Functional magnetic resonance imaging evidence of augmented pain processing in fibromyalgia. Arthritis Rheum 2002;46:1333-43.
- Cook DB, Lange G, Ciccone DS, Liu WC, Steffener J, Natelson BH. Functional imaging of pain in patients with primary fibromyalgia. J Rheumatol 2004;31:364-78.
- Navarro A, Boveris A. The mitochondrial energy transduction system and the aging process. Am J Physiol Cell Physiol 2007;292:C670-C686.
- Cobine PA, Pierrel F, Bestwick ML, Winge DR. Mitochondrial matrix copper complex used in metallation of cytochrome oxidase and superoxide dismutase. J Biol Chem 2006;281:36552-9.
- Jaksch M, Paret C, Stucka R et al. Cytochrome c oxidase deficiency due to mutations in SCO2, encoding a mitochondrial copper-binding protein, is rescued by copper in human myoblasts. Hum Mol Genet 2001;10:3025-35
- Duncan C, White AR. Copper complexes as therapeutic agents. Metallomics 2012;4:127-38.
- Leary SC, Winge DR, Cobine PA. “Pulling the plug” on cellular copper: the role of mitochondria in copper export. Biochim Biophys Acta 2009;1793:146-53.
- Olsen NJ, Park JH. Skeletal muscle abnormalities in patients with fibromyalgia. Am J Med Sci 1998;315:351-8.
- Bengtsson A, Henriksson KG. The muscle in fibromyalgia–a review of Swedish studies. J Rheumatol Suppl 1989;19:144-9.
- Carlson LA. Nicotinic acid: the broad-spectrum lipid drug. A 50th anniversary review. J Intern Med 2005;258:94-114.
- Depeint F, Bruce WR, Shangari N, Mehta R, O’Brien PJ. Mitochondrial function and toxicity: role of B vitamins on the one-carbon transfer pathways. Chem Biol Interact 2006;163:113-32.
- Hageman GJ, Stierum RH. Niacin, poly(ADP-ribose) polymerase-1 and genomic stability. Mutat Res 2001;475:45-56.
- Wimalawansa S J. Nitric oxide: new evidence for novel therapeutic indications Expert Opinion on Pharmacotherapy 2008. 9(11):1935-1954 Link
- Schuschke DA, Percival SS, Saari JT, Miller FN.(1999) Relationship between dietary copper concentration and acetylcholine-induced vasodilation in the microcirculation of rats. Biofactors. 10(4):321-7.
- Schuschke DA, Saari JT, Miller FN.(1995)A role for dietary copper in nitric oxide-mediated vasodilation.Microcirculation. 1995 Dec;2(4):371-6.
- Falcone JC, Lominadze D, Johnson WT, Schuschke DA.(2008) Endothelial cell-derived nitric oxide mobilization is attenuated in copper-deficient rats. Appl Physiol Nutr Metab. 33(6):1073-8.
- Qin Z, Gongora MC, Ozumi K, Itoh S, Akram K, Ushio-Fukai M, Harrison DG, Fukai T. (2008) Role of Menkes ATPase in angiotensin II-induced hypertension: a key modulator for extracellular superoxide dismutase function. Hypertension.52(5):945-51.
- Cagnie B, Dhooge F, Van Akeleyen J, Cools A, Cambier D, Danneels L.(2012) Changes in microcirculation of the trapezius muscle during a prolonged computer task. Eur J Appl Physiol.112(9):3305-12
- Larsson R, Oberg PA, Larsson SE(1999) Changes of trapezius muscle blood flow and electromyography in chronic neck pain due to trapezius myalgia. Pain. 79(1):45-50.
- Strøm V, Røe C, Knardahl S.(2009) Work-induced pain, trapezius blood flux, and muscle activity in workers with chronic shoulder and neck pain. Pain.144(1-2):147-55.
- Larsson B, Rosendal L, Kristiansen J, Sjøgaard G, Søgaard K, Ghafouri B, Abdiu A, Kjaer M, Gerdle B.(2008) Responses of algesic and metabolic substances to 8 h of repetitive manual work in myalgic human trapezius muscle. Pain. 140(3):479-90.
- Sjøgaard G1, Rosendal L, Kristiansen J, Blangsted AK, Skotte J, Larsson B, Gerdle B, Saltin B, Søgaard K.(2009) Muscle oxygenation and glycolysis in females with trapezius myalgia during stress and repetitive work using microdialysis and NIRS. Eur J Appl Physiol. 108(4):657-69
- Elcadi GH, Forsman M, Hallman DM, Aasa U, Fahlstrom M, Crenshaw AG3.(2014) Oxygenation and hemodynamics do not underlie early muscle fatigue for patients with work-related muscle pain. PLoS One. 2014 Apr 22;9(4):e95582