Natural Compounds That Help Mitigate the Effects of Statin-Induced Myopathy

Last month, I wrote a post on the widespread use of statin drugs and the dangers associated with them. Statin associated myopathy and mitochondrial impairment are serious and wide-spread side effects of statin drugs.

As I stated previously, I strongly believe that people need to be actively involved in their own health care. This means embracing a healthy Mediterranean diet and lifestyle as well as cultivating a positive attitude. And it also means using appropriate botanical and nutritional support as needed.

A number of natural compounds have been shown to help mitigate the effects of statin associated myopathy and mitochondrial impairment. Those that I find most helpful include the following:

Rhaponticum (Leuzea carthamoides) and Anabolic Enhancing Ecdysteroids

Ecdysteroids are chemicals found in insects, certain water animals, and some plants. Because ecdysteroids have a similar structure to the male hormone testosterone, they are widely used by athletes as a dietary supplement for increasing strength and muscle mass and to improve athletic performance.

As far back as the 1970s, ecdysterone (an ecdysteroid) was reported to possess anabolic properties. When Russian scientists compared ecdysterone with the anabolic steroid dianabol, both were found to have a similar effect on muscle tissue.[1]

There is growing interest in the pharmaceutical and medical applications of ecdysone. Studies in vivo and in vitro demonstrate a wide range of beneficial effects in mammals, including anabolic, hypolipidemic, anti-diabetic, anti-inflammatory, and hepatoprotective.[2] In one study, researchers tested the effects of ecdysterone (5 milligrams per kilogram of bodyweight) on rats, and found that it triggered a faster rate of muscle growth than a similar dose of anabolic drugs.[3]

Ecdysteroids possess several favorable non-hormonal biological properties. The most interesting of these is the effect on degenerative diseases. Ecdysteroids exert adaptogenic action (protection of the organism against adverse stress factors) associated with anabolic, gastroprotective, and antioxidant properties.

A second group of favorable effects is the possibility of suppression of neurodegenerative processes and protection of the cardiovascular system (metabolic syndrome symptom suppression, antidiabetic activity, and protection of heart and blood vessels).[4] Studies show that ecdysteroids are cardioprotective and specifically aid in mitochondrial protection.[5]

The anti-inflammatory and antioxidant mechanisms of phytoecdysteroids also make them effective against various cancers. In addition, these compounds have demonstrated antimicrobial and hepatoprotective abilities.

Summary of Various Biological and Pharmacological Effects of Ecdysteroids

[6]

Rhaponticum (Leuzea carthamoides), rich in ecdysterone and other related anabolic compounds, is the most studied herb for its adaptogenic, anabolic and immunomodulatory effects.[7]

A 2009 review based on 117 literary sources discusses the current knowledge of traditional uses, chemistry, biological effects, and toxicity of this species. The extract preparations from the plant exhibit various additional biological effects, including antioxidant, immunomodulatory, anticancerogenic, antimicrobial, antiparasitic and insect repellent activities.[8]

Several different classes of compounds have been isolated from various parts of Rhaponticum. The main groups are steroids, particularly ecdysteroids, and phenolics (flavonoids and phenolic acids) along with polyacetylenes, sesquiterpene lactones, triterpenoid glycosides and terpenes (essential oil).

Resveratrol 

Resveratrol is a stilbenoid, a type of natural phenol, and a phytoalexin produced by several plants in response to injury or when the plant is under attack by pathogens, such as bacteria or fungi. Sources of resveratrol in food include the skin of grapes, blueberries, raspberries, mulberries, and peanuts. Researchers have used resveratrol to increase the lifespan of obese mice and found that the compound reversed nearly all of the changes in gene expression patterns found in mice on high calorie diets—some of which are associated with diabetes, heart disease, and other significant diseases related to obesity.[9] 

Numerous in vitro and in vivo studies have demonstrated the positive effects of resveratrol in cardiovascular diseases (CVD). The primary beneficial effects of resveratrol are cardioprotective, anti-hypertensive, vasodilatory, anti-diabetic, and improvement of lipid status.[10]

Stilbene compounds are part of a vast group of natural defense polyphenols occurring in many plant species. Plants biosynthesize their secondary metabolites for specific reasons. Resveratrol is a phytoalexin, a substance produced in response to abiotic stress. This substance exerts antimicrobial and antioxidant activities against phytopathogens and ozone or UV stress. Stilbene compounds can bind several classes of protein structures to elicit a variety of responses.[11]

In healthy mice, resveratrol has been shown to increase lifespan and was protective under conditions of diet-induced obesity. Induction of mitochondrial biogenesis via PGC-1α activation is a major contributor of the beneficial effects of resveratrol.[12],[13],[14]

Mice fed resveratrol had bigger and denser mitochondria amassed between adjacent myofibrils in their nonoxidative fibers. Growth of mitochondria was confirmed by increased mitochondrial size and mtDNA (mitochondrial DNA) content. The max VO2 rate (the maximum capacity to transport and utilize oxygen during incremental exercise) was much higher in the nonoxidative muscle fibers of mice given resveratrol, which means there was an increased oxidative capacity. All these factors imply that resveratrol increases the ratio of oxidative to nonoxidative muscle fibers.

Since resveratrol has the possibility to change muscle fibers to a dominance of oxidative type 1 fibers, it makes sense that this would improve endurance since these types of fibers have a higher resistance to muscle fatigue. Researchers found that mice given resveratrol outran a control group by almost twice the distance. This means that resveratrol greatly increases resistance to muscular fatigue due to increased mitochondrial activation and a conversion of muscle to slow twitch fibers.

In another laboratory study, resveratrol significantly improved exhaustive swimming time and produced dose-dependent decreases in serum lactate and ammonia levels and CK activity after a 15-minute swimming test. The improvement was related to increased energy utilization (as blood glucose) and decreased serum levels of lactate, ammonia, and CK. Therefore, resveratrol could be a potential agent that improves energy transfer with an anti-fatigue pharmacological effect.[15]

The intake of resveratrol, together with habitual exercise, is beneficial for suppressing age-related decline in physical performance. Research indicates that these effects are attributable, at least in part, to improved mitochondrial function in skeletal muscle.[16]

Resveratrol inhibits cardiovascular disease through multiple mechanisms:

  • Anti-platelet activity/anti-thrombin: lowers fibrinogen[17]
  • Improves endothelial function and inhibits LDL oxidation[18]
  • Inhibits platelet aggregation and enhances nitric oxide release[19]
  • Inhibits atherosclerosis and vascular inflammation[20],[21]
  •   Raises GSH, inhibits oxidative endothelial damage[22]
  • Improves blood flow in the brain by 30 per cent, reducing the risk of stroke[23]
  • Inhibits stroke – reduces MMP-9, a contributor to neuronal injury[24]
  • Improves chronic venous insufficiency – edema-protective (ankles and calf)[25]
  • Lowers homocysteine[26]
  • Potent cardioprotective agent. Cardioprotective effects may be due to a reduction of atrial natriuretic peptide and transforming growth factor-beta1, which are known to protect the heart from detrimental remodeling.[27]
  • Suppresses lipid peroxidation and significantly improves oxidative status and release of nitric oxide. Prevents hypertrophic and apoptotic consequences induced by high blood pressure.[28] 

Pterostilbene

Pterostilbene is a naturally occurring phytoalexin identified in several plant species, including the well-known Aruvedic herb Pterocarpus marsupium. Although resveratrol is well-known for its health promoting benefits, pterostilbene may be the superior stilbene compound. With respect to mitochondrial genes, studies show that more than 100 genes involved in diverse mitochondrial functions are up-regulated by pterostilbene treatment.

Pterostilbene affects the expression of a diverse group of genes involved in methionine metabolism, response to drug, transcription factor activity, and mitochondrion functions. Additional analyses indicate that many genes involved in lipid metabolism are also affected. The observed response of lipid metabolism genes is in agreement with the known hypolipidemic properties of pterostilbene mediated through the activation of PPARα.[29]

In one study, pterostilbene supplementation was tested on skeletal muscle adaptations to exercise training in rats. After 4 weeks, the pterostilbene supplemented group showed that exercise training resulted in significant increases in time-to-exhaustion, the proportion of slow-twitch fibers, muscular angiogenesis, and mitochondrial biogenesis in rats, and these effects induced by exercise training could be augmented by pterostilbene supplementation. The researchers concluded that pterostilbene promotes skeletal muscle adaptations to exercise training, thereby enhancing endurance capacity.[30]

Creatine

Creatine is a natural substance that improves strength, increases lean muscle mass, and helps the muscles recover more quickly during exercise. The body produces some of the creatine it uses. It also comes from protein-rich foods such as meat or fish, and from supplements. Creatine turns into creatine phosphate in the body, where it helps make adenosine triphosphate (ATP). ATP provides the energy for muscle contractions throughout the body.

Magnesium-creatine chelate supplementation has been shown to improve exercise performance[31] and allow runners to reach their physiological threshold later in exercise.[32]

“Creatine MagnaPower” (MP), a patented magnesium creatine chelate, provides the body with a readily available source of magnesium while also making creatine more active by protecting it from cyclization. This patented mineral amino acid chelate contributes to an overall positive effect on many functions, including a non-steroidal anabolic enhancing effect. Creatine MP also provides rehydration and endurance in times of physiological stress.[33],[34]

As noted above, creatine is essential for normal muscle function. Statins inhibit guanidinoacetate methyl transferase (GAMT), the last enzyme in the synthesis of creatine; thus, they decrease its intracellular content. Such decreased content could cause mitochondrial impairment since creatine is the final acceptor of ATP at the end of mitochondrial oxidative phosphorylation. Accordingly, ATP synthesis is decreased in statin-treated cells.

The myopathy induced by statins is characterized by an increased urinary creatine–creatinine ratio, although muscle-toxicity symptoms and biopsy evidence of mitochondrial dysfunction without creatine kinase elevation have been documented during statin therapy.[35]

There is an extensive and still growing body of literature supporting the efficacy of creatine supplementation.[36] Creatine supplementation prevents the opening of the mitochondrial permeability transition pore that is caused by statins. Clinically, creatine administration prevents statin myopathy in statin-intolerant patients.[37] 

In one study, serum levels of creatine kinase (CK) and muscle pain were treated with creatine supplementation. Muscle pain occurred and CK levels rose to abnormal levels when statins were prescribed, but not when the statin was prescribed together with creatine.[38]

CoenzymeQ10 (CoQ10)

Research shows that reduced synthesis of coenzyme Q10 may be the cause of statin related myopathy.[39] There are also indications that statins lead to a reduction of serum CoQ10 levels.[40] Fortunately, CoQ10 supplementation can partially mitigate statin related mitochondrial dysfunction.[41] In fact, the rationale for using CoQ10 to treat statin myalgias is so overwhelming that Merck & Co, Inc. pursued a patent for a CoQ10-statin combination product. They were issued two patents for this product, which was meant to counteract statin-associated myopathy and to reduce the elevated transaminase levels produced by the statin.[42]

Previous studies have demonstrated a possible association between the induction of CoQ10 after statin treatment and statin-induced myopathy. In a meta-analysis of randomized controlled trials investigating the effect of CoQ10 on statin-induced myopathy, researchers evaluated twelve randomized controlled trials with a total of 575 patients; 294 patients were in the CoQ10 supplementation group and 281 were in the placebo group.

Compared with placebo, CoQ10 supplementation ameliorated statin-associated muscle symptoms, such as muscle pain, muscle weakness, muscle cramp, and muscle tiredness, whereas no reduction in the plasma creatine kinase level was observed after CoQ10 supplementation.

The study concluded that CoQ10 supplementation ameliorated statin-associated muscle symptoms, implying that CoQ10 supplementation may be a complementary approach to manage statin-induced myopathy.[43]

Stabilized R-lipoic acid

Stabilized R-lipoic acid has been shown to reduce age-related mitochondria oxidative damage,[44] lower glucose and lactate,[45] improve metabolic activity, and lower oxidative stress and oxidative damage.[46]

BioEnhanced™ Na-RALA is a stabilized form of RLA that does not degrade at high temperatures, is more bioavailable than regular RLA, and has no solvent residues.  RLA can be converted, or reduced, to DHLA, or dihydrolipoic acid. These two forms of LA make up a “redox couple,” which means that each form can chemically change, or donate back and forth.

Clinical studies have shown that the use of stabilized R-lipoic acid works together with CoQ10, improving quality of life by preventing free radical damage to proteins.[47]

Disturbances in acid-base balance, such as acidosis and alkalosis, have the potential to alter the pharmacologic and toxicologic outcomes of statin therapy.[48]

Other studies have shown that statins may activate muscle atrophy genes, may increase muscle specific NO‐synthetase and NO production, and may decrease fatty acid oxidation.[49],[50]

Patients experiencing muscle pains on statins were 11-times more likely to be a heterozygous carrier for the carnitine palmitoyltransferase-2 deficiency, and 31% of muscle biopsies evaluated had carnitine abnormalities. Moreover, patients were 20-times more likely to be carriers for McArdle’s disease (a glycogen storage disease), and a third had lipid storage problems. This trial suggests that people who experience muscle pains on a statin are more likely to have an underlying metabolic muscle disease with the symptoms of statin muscle pain being brought out in these carriers. Furthermore, almost 50% of the analyzed samples had CoQ10 levels that were 2–4 standard deviations below normal. Therefore, supplementing with both CoQ10 and l-carnitine may be a rational approach to treating certain statin myalgias.[51]

Some patients are susceptible to statin-induced myopathy due to variations in genes encoding proteins involved in statin uptake and biotransformation such as the solute carrier organic anion transporter family member 1B1 (SLCO1B1) or cytochrome P450 (CYP2D6, CYP3A4, CYP3A5). Carriers for carnitine palmitoyltransferase II deficiency and McArdle disease also present with higher prevalence of statin-induced myopathy.[52]

Vitamin D

A recent study evaluated whether vitamin D status modifies the association between statin use and musculoskeletal pain in a sample representative of the general population. In the study, musculoskeletal symptoms and statin use were self-reported. Vitamin D status was assessed using serum 25 hydroxyvitamin D (25[OH]D), categorized as <15 ng/mL or ≥15 ng/mL. To evaluate if vitamin D status modifies the association between statin use and prevalent musculoskeletal pain, the researchers performed multivariable-adjusted logistic regression models stratified by 25(OH)D status.

Among 5907 participants ≥40 years old, mean serum 25(OH)D was 23.6 ng/mL. In stratified multivariable-adjusted logistic regression models, individuals with 25(OH)D <15 ng/mL using a statin had significantly higher odds of musculoskeletal pain compared to those not using a statin. Among those with 25(OH)D ≥15 ng/mL, there was no significant association between statin use and musculoskeletal pain.

The study concluded that among adults ≥ 40 years old with 25(OH)D <15 ng/mL, statin users had nearly 2 times greater odds of reporting musculoskeletal pain compared to non-statin users. This supports the hypothesis that vitamin D deficiency modifies the risk of musculoskeletal symptoms experienced with statin use.[53]

Supplementing with Vitamin D

  • It’s best to supplement with a food grown form of vitamin D that also includes a small amount of vitamin K (K-1 or K-2, or both), and vitamin A. Vitamin D grown in saccharomyces cerevisiae, creates a vitamin D food-like matrix and contains various immune-enhancing compounds such as β-glucan, nucleic acids, mannan oligosaccharides and chitin. This has been proven to enhance immune response and growth.
  • Simply taking extra vitamin D is not the correct approach. Instead, the appropriate amount must be provided to maintain serum levels in a healthy range of 25 OH (>45 <80).
  • Always check both forms of vitamin D; that means 25-OH and 1,25 dihydroxyvitamin (di OH). While 1,25 vitamin D is the most potent vitamin D metabolite, 25-OH vitamin D levels more accurately reflect vitamin D status because parathyroid hormone and other hormones do not influence it. If you only check 25-OH after supplementing with vitamin D, and the levels don’t increase, proceed by checking the 1,25 di OH level and the parathyroid hormone level. If these are either high normal, or elevated out-of-range, then you need to seek a professional skilled at normalizing vitamin D levels.

Curcumin

Curcumin is the polyphenolic ingredient of Curcuma longa, which has numerous pharmacological properties against a vast range of diseases. Curcumin has several mechanisms of actions relevant to the treatment of SIM. These include the capacity to prevent and reduce delayed onset muscle soreness by blocking the nuclear factor inflammatory pathway, attenuation of muscular atrophy, enhancement of muscle fiber regeneration following injury, and analgesic and antioxidant effects.

Curcumin can also increase the levels of cyclic adenosine monophosphate, which leads to an increase in the number of mitochondrial DNA duplicates in skeletal muscle cells. Finally, because of its essential lipid-modifying properties, curcumin is a possible adjunct to statin therapy in patients with SIM, assisting in lowering of low-density lipoprotein cholesterol and potentially reducing the dose of statins.[54]

Cistanche (Herba Cistanches)

Cistanche is a parasitic plant that is commonly is used in Traditional Chinese Medicine (TCM) for treating kidney deficiency, impotence, female infertility and Age-related constipation. Recent research suggests that cistanche may be protective against simvastatin-induced muscle toxicity.[55],[56]

Yang xin shi

The Yang xin shi tablet (YXST) is prescribed in TCM for improving the clinical symptoms of patients with cardiovascular diseases in combination with conventional drugs.

YXST Ingredients

YXST can effectively inhibit the myolysis induced by the statin drug Simvastatin. Mitochondrial activities are closely related to energy production. In studies, YXST was shown to significantly increase the activity of mitochondrial complex III and glycogen utilization to counteract the side effects of statin in the skeletal muscle.[57]

Potassium Bicarbonate

Research indicates that potassium bicarbonate improves endothelial function, cardiovascular risk factors, and bone turnover in mild hypertensives.[58]

Supplementing with potassium bicarbonate has been shown to prevent statin-induced myopathy and further demonstrates a preventive effect on statin (cerivastatin)-induced increase in CPK concentrations.[59]

Choosing a Natural Approach

Achieving healthy cholesterol levels can generally be accomplished through attention to a healthy Mediterranean diet, regular exercise, and appropriate supportive supplements, such as those discussed here.

Because of unique individual differences, optimizing cholesterol levels may require consultation with a health care professional skilled in the use of nutritional and botanical supplements.

God embraces you as you are—shadow and light, everything. God embraces it, by grace. —Brother David Steindl-Rast

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Statin-Associated Myopathy and Mitochondrial Impairment

If we knew what it was we were doing, it would not be called research, would it?” Albert Einstein

Part One

I’m often asked if I think statin drugs are useful. Of course it’s important first to address the issue of cholesterol levels which statin drugs are used to control. I recently wrote a blog entitled “What can Centenarians teach us about cholesterol levels and longevity – It isn’t what you think” in which I provided substantial evidence questioning the current guidelines regarding what is actually a healthy total cholesterol level.

As far as statins go, my opinion is that if people are willing to be involved in their own healthcare by adopting a comprehensive approach to health optimization—which includes a healthy diet and lifestyle, the support of appropriate botanical and nutritional medicines, and a positive attitude—then I see little to no need for statin drugs. 

However, if you do feel the need to take a statin, then I will provide you with essential supportive care to both mitigate the adverse effects of statins and to potentiate them, so that a reduced amount might be sufficient.

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