Drug-induced myopathies are classified as acquired myopathies caused by exogenous factors. These pathological conditions develop in patients without muscle disease and are triggered by a variety of medicaments, including lipid-lowering drugs (LLDs), neuroleptics, anticancer agents, antibiotics, corticosteroids, antivirals, and many others 
. Drug-induced myopathies arise as a side effect of drug therapy intended to target a medical condition not directly related to muscle symptoms. These kinds of myopathies are manifested by muscle disorders which can be defined by the common term myotoxicity. This problem affects many groups of patients and its consequences could be fatal.
The term drug-induced myopathy is very broad, covering an extensive spectrum of symptoms ranging from myalgia (muscle pain or weakness without creatine kinase, CK, elevation), myositis (muscular complaints with CK elevation) to extremely serious symptoms associated with necrosis or rhabdomyolysis. The mechanisms underlying drug-induced myopathies are very diverse and can include direct muscle damage caused by mitochondrial injury or immune-mediated inflammatory damage 
Hyperlipidaemia is the most common dyslipidaemia. It is a pathological condition manifested by abnormal amounts of lipids (e.g., triglycerides, cholesterol, fatty phospholipids). Hyperlipidaemia is defined as abnormally elevated levels of any or all lipids and lipoproteins in the blood. This includes hypercholesterolaemia characterized by high cholesterol levels in the patient’s blood. Dyslipidaemia therapies are based on the use of various LLDs which include statins, fibrates, niacin, bile acid sequestrants, ezetimibe, lomitapide, phytosterols, omega-3 supplements, and PCSK9 inhibitors 
. Widely used LLDs, intended to reduce the risk of cardiovascular diseases (CVD), have been the most commonly reported drugs to be associated with the adverse effects manifested by myotoxicity 
3. Models for Study of Lipid-Lowering Drug-Induced Myopathies
The LLD-induced myotoxicity assessments were conducted using a variety of models including cell lines and mammalian organisms (e.g., mouse, rat, goat, rabbit, and dog) (Table 1). Among various LLDs, statins are the most commonly applied in humans for the prevention and treatment of CVD. Therefore this group of drugs gain special attention from researchers 
In-vitro research using human and murine cell lines provides new data concerning LLD-induced myotoxicity and confirmed differences in the side effects caused by LLDs belonging to the same group (e.g., statins). This kind of research also helps to examine compounds which could protect cells exposed to LLD treatment. For example, recent studies carried out on mouse C2C12 skeletal muscle cells shed more light on the molecular mechanisms of the cytoprotective effect of geranylgeraniol (GGOH), a mevalonate-derived isoprenoid. GGOH protects cells treated with statins, precisely ATV and SIM, through the inhibition of calpains, which are calcium-dependent, nonlysosomal cysteine proteases 
. Moreover, these experiments revealed that different statins, depending on the degree of their lipophilicity, cause more (SIM, higher lipophilicity) or less (ATV, lower lipophilicity) myotoxicity manifested in impaired cellular mitochondrial respiration. Notably, studies conducted on a rodent model of statin-induced myalgia have also confirmed that the administration of GGOH can prevent skeletal muscle fatigue 
Studies on cell lines have also provided a lot of valuable information regarding the molecular mechanism of LLDs’ mechanism of action, which has proven to be very complex. Specifically, primary human muscle cells exposed to a lipophilic SIM and hydrophilic rosuvastatin (RSV) display various changes in their metabolism, and gene and protein expression profiles (regarding more than 1800 mRNA transcripts and 900 proteins). In addition to its well-documented effects on cholesterol biosynthesis, treatment with both investigated statins causes changes in profiles of eicosanoids secreted by human muscle cells. It also disrupts their proliferation and differentiation. Furthermore, results of the study support the hypothesis that supplementation with omega-n fatty acids (eicosanoids precursors) might be beneficial as a prevention or as a treatment for patients undergoing statin therapy 
To meet the needs arising from the necessity to study LLD-induced myotoxicity, researchers continue to refine existing tools and develop new ones. An example is a microphysiological system based on patient-derived myoblasts. The cells form engineered myobundles mimicking the organization and function of native skeletal muscle, allowing for the study of skeletal muscle ex vivo development 
. The system was used to investigate the statin-associated musculoskeletal symptoms 
. Statin exposure leads to myotoxicity manifested in the reduction of cells’ contractile force, and disruption of sarcomeric actinin organization.
Data gained via in-vitro experiments, despite their undisputed advantages, are limited in terms of predicting in-vivo conditions and are not able to replicate the behaviour of cells in an entire living organism. Therefore, in-vivo studies conducted on more complex model organisms such as a mouse are thought to provide more valuable and reliable information regarding the effects of progression of particular diseases, and their treatment. Osaki et al. (2015) developed skeletal muscle-specific HMGCR knockout mice which were intended to mimic human post-statin myopathy conditions 
. The generated model exhibited severe myopathy caused by the deficiency of HMGCR enzyme activity and resulting in depletion of mevalonic acid (MVA). In HMGCR knockout mice, induction of skeletal muscle cell membrane damage, myofibrils necrosis, and an elevated serum CK level were observed. Oral administration of MVA revealed that the generated model was completely rescued 
As mentioned in the previous chapter, also genetic polymorphisms are risk factors for LLD-induced myotoxicity. Research related to this phenomenon was conducted using transgenic mouse models carrying different slow-channel congenital myasthenic syndrome (SCS) mutations 
. The results demonstrated that one of the genetic variants of the nicotinic acetylcholine receptor (nAChR) could be related to the onset of statin-induced side effects. The nAChR is a transmembrane glycoprotein expressed in skeletal muscle at neuromuscular junctions (NMJs), which transduces the chemical signal necessary for muscle contraction. Studies revealed that mice expressing a mutant variant of nAChR (SNP rs137852808; αC418W) display impaired neuromuscular transmission upon ATV treatment. The study provides an important clue to explain one of the most common statin side effects regarding neuromuscular problems contributing to muscle pain or weakness 
The histopathological changes, comprising hypercontraction and fibre necrosis, in muscle exposed to statins have also been examined using a rat model. Studies on rats have confirmed the distinct susceptibility of skeletal muscle to damage caused by therapy with different statins (more severe in the case of lipophilic SIM and lovastatin (LOV) than hydrophilic pravastatin [PRA]). Moreover, it was also reported that young rats are more susceptible to statin-induced muscle damage than adults 
Further investigations conducted on female rats revealed that type II muscle fibres (primarily glycolytic and poor in mitochondria) are most vulnerable to muscle injury caused by statins 
. However, other research groups using young male rats obtained contrary results. According to their outcomes, the CER-induced myotoxicity affects only type I, but not type II fibres 
. This suggests that susceptibility to muscle-related side effects induced by LLD therapy depends on additional factors such as age and/or gender.
Studies carried out on a rat model also made it possible to establish some details regarding molecular mechanisms underlying statin-induced myopathy 
. The obtained results showed that SIM down-regulates PI3k/Akt signalling, and up-regulates FOXO transcription factors. The latter is followed by an increase in the transcription of genes implicated in proteasomal- and lysosomal-mediated protein degradation, such as MAFbx
. Studies also revealed impairment of carbohydrate oxidation, the occurrence of oxidative stress, inflammation, and increased plasma CK level. Muscle necrosis appeared in the group of animals exposed to the longest statin treatment 
Further, proteomic analyses using a rat model have provided valuable information on the effects of LLDs, represented by statins (ATV, and fluvastatin, FLV) and fibrates (fenofibrate), on the expression profiles of treated skeletal muscle 
. The mentioned analyses focused on the expression levels of proteins crucial for skeletal muscle functions, such as proteins associated with energy production systems (including oxidative and glycolytic enzymes and CK), heat shock proteins (providing protection against oxidative stress), and proteins that are components of myofibrils. Proteomic examination demonstrated that all treatments induced a general tendency to down-regulation of protein expression. 
The rabbit is also one of the animal models used to study myotoxicity phenomena caused by LLD exposure. Studies in this species have confirmed data gained from other models and provided an interesting insight into the muscle pathology induced by LLDs 
. Treatment with statins leads to necrosis and degeneration of rabbit muscle fibres. Ultrastructural examination allowed the accompanying changes to be described in more detail, revealing the presence of autophagic vacuoles and swollen mitochondria, as well as disruption of myofibrils and Z-bands 
The goat is gaining acceptance as an established model for biomedical studies and research with environmental relevance. This is mostly related to methane emissions caused by ruminants. Methane is one of the major greenhouse gases and its emission influences the climate. Its enteric formation is a by-product of the digestive process of ruminants and directly results from the activity of anaerobic bacteria. The reduction of methane emission is currently one of the significant challenges worldwide. Various measures are being used for this purpose, including LOV supplementation of animals, such as goats 
. Therefore, due to the side effects caused by statins, the influence of these compounds on goat skeletal muscle began to be studied 
. The histology studies revealed the occurrence of LOV-induced goat muscle damage correlated with increasing dosages. Moreover, the proteomic analysis showed that LOV triggers complex modifications to carbohydrate metabolism, energy production, and muscular system development 
. This shows how important it is to evaluate side effects when studying the use of known substances in new models or for new purposes.
The dog has proven to be an excellent model corresponding to human diseases. Kawata and Yokoi (2019) carried out studies to explain the effects of LOV and fenofibrate on a dog’s skeletal muscles 
. Oral co-administration of LOV and fenofibrate caused skeletal muscle injury. Similarly to other animals tested in this respect, in the skeletal muscles but not in cardiomyocytes, elevated levels of CK and necrosis of skeletal muscle fibres were observed. Also, the conducted research also provides an interesting implication for examination and validation of non-invasive biomarkers of clinical drug-induced side effects. One of the proposed biomarkers of LLD-induced skeletal muscle injury is an increased level of miR-1 in plasma. miR-1 is a representant of microRNA particles, which are small non-coding RNAs, characterized by high stability in blood and muscle expression pattern 
The use of a variety of established and reliable animal research models enables the discovery of novel properties of well-characterized compounds, as exemplified by statins. These drugs appear to be a particularly interesting group of LLDs because, in light of unorthodox research on the development of therapies for Duchenne muscular dystrophy (DMD) based on statins, their dual nature regarding their effects on skeletal muscle function has been revealed 
. DMD is the most common and severe form of lethal muscular dystrophy caused by mutations in the dystrophin gene. SIM seems to have a positive impact on the skeletal muscle of dystrophic (mdx) mice, dramatically reducing damage and enhancing their function. These improvements are accompanied by autophagy activation, a recent therapeutic target for DMD, and less oxidative stress 
As stated above, models provided insight into the pathogenesis of LLD-induced myotoxicity. The in-vitro studies and research on mammalian model organisms reveal a wide range of data regarding the treatment of diseases induced by LLDs. Despite the many advantages of in-vitro and mammalian models, their research use has some limitations, e.g., results obtained from in-vitro tests do not always reflect in-vivo processes, and in the case of animal models, the number of individuals in the litter does not allow for reliable statistical analysis. This makes the development of new models and further in-depth research necessary.