As cholesterol synthesis is comparatively lower in skeletal muscle relative to other organs, it is thought to be dependent on serum uptake. The fibroblast LDL receptor appears to be half-saturated at subphysiological levels of LDL, around 30 μg/mL and deletion of this receptor doesn't appear to influence intracellular cholesterol significantly.
Inhibition of HMG-CoA (statin usage) is able to induce SREBP2 in adipose and liver cells to increase cholesterol uptake via increasing the expression of the LDL receptor and the liver's upregulation is known to reduce circulating LDL-C via increased uptake.
Other mechanisms of cholesterol uptake from LDL-C include the lipoprotein lipase (LPL) receptor which although is the rate-limiting enzyme for triglyceride uptake into a cell is not the rate-limit for cholesterol uptake; at least with simvastatin, muscle cells can uptake 30% more cholsterol following statin usage (mouse study) without affecting cholesterol concentrations. This study, despite failing to note an increase in cholesterol concentrations alongside the increased uptake, noted that simvastatin increased mitochondrial content of skeletal muscles; although due to decreases in ubiquinone this may be a false positive for mitochondrial function. Increased cholesterol concentration, however, has been noted in human interventions with simvastatin at 80mg and this study noted that other sterols, such as campesterol, also increased.
It should be noted that gross overexpression of LPL in skeletal muscle may cause a myopathy, though to be related to increased fatty acid influx (as LPL mediates fatty acids and cholesterol) similar to an increase in LPL on cardiomyocytes. Furthermore, competitive athletes who have increased LDL expression seem to be more likely to have complications from statin usage.
Cholesterol uptake into skeletal muscle cells (myocytes) appears to be mediated by both LPL and the LDL receptor, with statin usage increasing the activity of the LDL receptor
Phenotypically speaking, statin-induced myopathy appears to be a deficiency in the regenerative capacity of microlesions which is supported by increased serum creatine kinase (indicative of muscle protein breakdown) up to 48-72 hours after tissue damaging exercise and how intense exercise is an independent risk factor for statin induced myopathy.
Lovastatin is an HMG-CoA reductase inhibitor, preventing the conversion of HMG-CoA into Melavonate (rate limiting substrate in cholesterol synthesis); the Mevalonate pathway proceed unilaterally until it reaches the substrate Farsenyl Pyrophosphate (FPP) where it can then branch off into several alternate pathways. Although inhibition of HMG-CoA reduces all of these pathways, restoring cholesterol synthesis after this locus point by introducing squalene or cholesterol itself does not attenuate myopathy (using ATP reductions as a surrogate marker) while this myopathy appears to be dependent on reduced Geranylgeranyl Pyrophosphate (GGPP). GGPP is thought to be a main target molecule for statin-related myopathy as it is already expressed to a lower degree in skeletal muscle which may explain the relative sensitivity for complications in skeletal muscle relative to other organs (although cholesterol synthesis is inherently lowest in heart and skeletal muscle tissue, myopathy appears to be independent of reduced cholesterol concentrations).
Less GGPP in a cell system is associated with less protein synthesis due to reduced RhoA (a small protein kinase) and may inhibit complex IV of the mitochondria, reducing cellular ATP levels. RhoA is known to be reduced due to less Melavonate availability and lower RhoA concentrations are associated with muscle cell catabolism.
Myopathy from lovastatin appears to be associated with reducing GGPP (a consequence of inhibiting HMG-CoA, the target enzyme of statins) and independent of the reduction in cholesterol per se
Lovastatin is also known to induce atrogin-1, a protein that mediates protein catabolism and this induction of atrogin-1 is ablated by excessive incubation of PGC-1a.
One study (otherwise healthy men aged 60-69) that noted that cholesterol was linearly associated with more lean mass gain in older individuals on a standardized diet and given resistance training noted that usage of lovastatin (in the recommended range) was associated with more muscle building than persons not using statins; this study noted comparable increases with lovastain and pravastatin, both of which outperformed atorvastatin and simvastatin which comparatively outperformed no statin usage. The authors hypothesized this was a recompensatory effect from the known ability of statin drugs to augment exercise-induced muscle injury as assessed by marathons or downhill treadmill walking and when measured 48-72 hours after (intense exercise is also an independent risk factor for myopathy from statins, suggestive of augmenting muscle damage or attenuating the rate of repair).
One study suggests that chronic usage of statin drugs and pairing statins with exercise can increase lean mass accrual from exercise, apparently synergistic with dietary and serum cholesterol. Although statins during exercise are not well studied, they appear to reduce the rate of muscle regeneration
The connection between GGPP and RhoA is unlikely to explain the observed reactions as there are differences between lovastatin and pravastatin, as the latter is known to not be taken up into myocytes to a large degree due to being selectively taken up by OATP1B1, a transport expressed on hepatocytes almost exclusively; thus limiting the muscle exposure to pravastatin. Although pravastatin would induce the same effects if cultured in vitro, it does not appear to reach skeletal muscle well after ingestion.
The only possible link here is that cholesterol ester and free cholesterol influx into a cell (thought to be anabolic to skeletal muscle) is inversely dependent on RhoA, being increased with lower RhoA concentrations.
Reductions of GGPP and, subsequently, RhoA are a possible explanation for the observed hypertrophic response to statins but cannot explain the difference between pravastatin and lovastatin; these reductions are also inherently catabolic
Another possible explanation is using Selenoproteins (proteins made with selenium as a component) and particularly Selenoprotein N, encoded by the SEPN1 gene; due to HMG-CoA inhibition, there is less isopentenylpyrophosphate (IPP) availability (in the cholesterol biosynthetic chain after mevalonate) and IPP appears to be critical for a selenocysteine transfer RNA to make selenoproteins.
SEPN1-related myopathies (genetic faults) are phenotypically similar to statin-induced myopathies and the reduced amount of selenoprotein N (which is localized in the endoplasmic reticulum of muscle and accumulates in damaged muscle and recruit satellite cells) correlates well with the phenotype observed in statin-induced and SEPN1 related myopathy as the observed reduced rate of tissue regeneration (evidence by lovastatin increasing serum creatine kinase 48-72 hours after exericse, but not immediately after) is more indicative of reduced repair rates than of inducing damage.
Furthermore, although ablation of SEPN1 and reduced selenoprotein N is not adverse to muscle growth per se and is not present in high levels in adult skeletal muscle without physical injury, introduction of a mutant selenocysteine tRNA to reduce selenoprotein amounts, in rats, is associated with a 50% increase in muscle protein synthesis that is mTOR and exercise dependent.
Selenoprotein deficiency appears to be somewhat related to both myopathy as well as enhanced exercise-induced hypertrophy, and statins may reduce cellular selenoprotein concentrations. This seems to correlate better with the observed effects of statins on muscle protein synthesis, but assumes that a hormetic response occurs (this hypothesized hormetic response that ultimately builds muscle is not known yet)
Thyroid deiodinases are selenoproteins, which appears to generally be reduced following statin induced inhibition of HMG-CoA by limiting the amount of IPP available for selenocysteine tRNA. Despite this, it has been noted that lovastatin and IPP inhibitors increase the activity of type 2 iodothyronine selenodeiodinase (D2) in brown adipose tissue of mice and in vitro
In hypothyroid patients, there appears to be some case studies noting a decrease in T4 and increase in TSH in response to lovastatin paired with thyroxine which has been seen in rats (simvastatin) although failed to be replicated with simvastatin.
Red yeast rice which contains monacolin (especially monacolin K) lowers cholesterol levels by reducing cholesterol synthesis by the liver through inhibiting the rate-limiting step catalyzed by the enzyme 5-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA). However, since monacolin K is identical to the pharmaceutical known as lovastatin, the FDA has banned sales of red yeast rice which contain non-negligible quantities of monacolin K since it is a "non-approved drug", thus red yeast rice as currently marketed in the US may not have these effects on the liver's cholesterol production. However, a study done after the FDA ban found that many red yeast rice products still contain monacolin K at levels which widely vary, and a Freedom of Information Act request to investigate FDA oversite of monacolin K levels has revealed that FDA enforcement of monacolin K levels is lacking.
Ubiquinone concentrations in skeletal muscle are known to be reduced with statin usage such as simvastatin (80mg for 8 weeks resulting in a 33.6% reduction) paired with less repiratory chain activity.
One study using high dose (80mg) simvastatin and measuring sterol concentrations in muscle cells noted that, despite an increase in cholsterol, dietary campesterol (naturally occurring and common sterol) increased; suggesting statin-induced sterol uptake is general rather than specific to cholesterol. Coingestion of plant sterols (or stanols) with statin usage appears to induce further decreases in serum cholesterol.
Schweinfurthins appear to be synergistic with lovastatin in reducing levels of GGPP in medium.
Citrinin, a mycotoxin found in red yeast rice, has been shown to be genotoxic to human lymphocyes at high concentrations (above 60μM) in vitro and mutagenic at concentrations above 0.2μg/g in a Salmonella-hepatocyte assay.
There have been several reports of side effects traditionally associated with statin therapy seen with red yeast rice, such as myopathies (including rhabdomyolysis) and hepatitis.