Skip to content
Publicly Available Published by De Gruyter May 16, 2023

Safety monitoring of drug-induced muscle injury and rhabdomyolysis: a biomarker-guided approach for clinical practice and drug trials

  • Patryk Ostrowski , Michał Bonczar ORCID logo , Aida-Elena Avram , Giuseppe Lippi ORCID logo and Brandon M. Henry EMAIL logo


Skeletal muscle tissue (SKM) may be damaged due to mechanical, metabolic, and exertional causes. However, drug-induced myopathy is among the most frequent causes of muscle disease. The clinical picture of drug-induced myopathies may be highly variable. It may present as asymptomatic or mild myalgias, with or without muscle weakness, which are likely underreported. However, it may also appear as chronic myopathy with severe weakness and, rarely, even as massive rhabdomyolysis with acute kidney injury (AKI). Unfortunately, the available biomarkers for SKM injury do not fully meet the needs for satisfactory detection of drug-induced damage, both in clinical and research settings, mainly due to their low sensitivity and specificity. Therefore, the present study proposes a strategy for drug safety monitoring using the available biomarkers of SKM injury. Moreover, we will discuss mechanisms of drug-induced SKM injury, traditional laboratory testing for SKM injury, and novel skeletal myocyte biomarkers under investigation. This can be incredibly useful in both clinical practice and for de-challenge/re-challenge investigational trials where the risk of drug-induced SKM injury is present.


Skeletal muscle tissue (SKM) may be damaged due to mechanical, metabolic, and exertional causes. However, drug-induced myopathy is among the most frequent causes of muscle disease [1]. The clinical picture of drug-induced myopathies may range from asymptomatic or mild myalgias, with or without muscle weakness, which are likely underreported, to chronic myopathy with severe weakness and rarely, even to massive rhabdomyolysis with acute kidney injury (AKI) [1]. Rhabdomyolysis is a syndrome defined by muscle necrosis and release of cell degradation products and intracellular elements within the bloodstream and the extracellular space [2].

Drug-induced myopathies may result from various mechanisms. These include direct myotoxicity (caused by alcohol, cocaine, glucocorticoids, and statins, amongst others), immunologically-induced inflammatory myopathy (caused by D-penicillamine, statins, and anti-cancer drugs), and indirect SKM injury (occurs as a result of a variety of different mechanisms). However, the complete etiology of drug-induced myopathies remains unclear.

In clinical practice, as well as during drug development and in clinical trials, the diagnosis of SKM injury can be challenging due to the variable symptomology, reliance on patient-self reporting, and lack of highly specific biomarkers, such as those available for cardiac myocyte injury (i.e., cardiac troponins) [3]. Such factors make the prediction of SKM-related adverse events challenging to predict for both new investigational agents and establishing approved therapeutics. Moreover, the rapid rise of new therapeutics with the potential to cause SKM injury, such as immunotherapies and targeted therapies, as well as new treatments (such as gene therapy) specifically targeting muscular or neuromuscular diseases, demands an improved clinical strategy to identify myocyte injury and enable appropriate and timely clinical intervention.

While statins have been the prototypical drug associated with SKM injury, checkpoint inhibitors, which have revolutionized cancer treatment and are now being investigated in thousands of clinical trials and approved for the treatment of diverse cancer types [4], are likely to become among the leading causes of drug-induced necrotizing and immune-inflammatory myopathies [5]. In addition, checkpoint inhibitors are more frequently being employed in combination with other agents (including with other checkpoint inhibitors) in clinical practice, as well in hundreds of combination drug trials with other novel biological, targeted, and immunotherapies. The use of checkpoint inhibitors in combination therapy further complicates the safety monitoring of SKM injury due to the potential for drug-drug interactions. This is particularly a concern in early-phase trials, where checkpoint inhibitors may possibly enhance the SKM injury potential of a novel investigational agent or vice versa, leading to increased toxicity and presenting a challenge to investigative teams to distinguish the causal agent(s) and institute appropriate safety countermeasures (i.e., dose reduction of the offending agent, etc.).

In this paper, we will discuss mechanisms of drug-induced SKM injury, traditional laboratory testing for SKM injury, novel skeletal myocyte biomarkers under investigation, and propose a strategy for drug safety monitoring in oncology clinical practice and for de-challenge/re-challenge investigational trials where the risk of drug-induced SKM injury is present.

Mechanisms of drug-induced skeletal muscle injury

Drug-induced SKM injury may result from various mechanisms. However, they have been divided into three main groups, namely direct myotoxicity, immunologically induced inflammatory myopathies, and indirect SKM injury. The variable pathomechanisms of drug-induced SKM damage and their histological characteristics are presented in Table 1.

Table 1:

General, historical, and under investigation biomarkers of skeletal muscle injury.

Pathomechanism Drugs Histological characteristics
Necrotizing myopathy/rhabdomyolysis Statins, fibrates, alcohol, heroin General necrosis of SKM tissue, with or without signs of regeneration
Immune-inflammatory myopathies Statins, checkpoint inhibitors, alfa-interferon, TNF-alpha inhibitors, vascular endothelial growth factor inhibitors, D-penicillamine Multifocal clusters of necrotic fibers (Checkpoint inhibitors)
Mitochondrial myopathy Antiretrovirals, statins, clevudine A potential presence of inflammatory changes in SKM (antiretrovirals, statins)
Lysosomal/autophagic myopathies Chloroquine, hydroxychloroquine, amiodarone, perhexiline Intra-lysosomal complexes, autophagic degeneration of myofibers
Concentric lamellar structures (myeloid bodies) and curvilinear bodies are present in the cytoplasm of striated muscle fibers
Catabolic myopathy with type 2 fiber atrophy Corticosteroids Nonspecific type 2 fiber atrophy
Myofibrillar myopathies Emetine Generalized atrophy of both fiber types
Lesions of the sarcomeres
Granular breakdown of myofilaments and sarcomeres
Formation of cytoplasmic bodies
Microtubular myopathies Colchicine, vincristine Accumulation of lysosomes and autophagic vacuoles without necrosis

Direct myotoxicity

Direct myotoxicity concerns drugs that have a direct toxic effect on myocytes and their organelles [6]. A large number of different therapeutics have been shown to damage SKM directly.

Statin-associated myopathies

Statins have been associated with numerous muscle disorders, with a variable range of severity. The mildest symptoms may include mild myalgias and muscle cramps [5]. However, cases of severe rhabdomyolysis have also been reported in the past [7]. In addition, it has been stated that statins induce direct toxicity in both the sarcoplasmic reticulum and the mitochondria, or more specifically, on their membranes, causing necrotizing and mitochondrial myopathies [8]. The frequency of statin-induced myopathy has been reported to occur in 2–3 out of every 100,000 patients [9].

Corticosteroid-induced myopathies

Myopathies have been observed in patients treated with both short-, and long-term corticosteroid therapy [10]. Various reports have also stated that corticosteroid-induced myopathy is one of the most prevalent drug-induced myopathies, with a frequency ranging between 50 and 60 % among patients using corticosteroids for a prolonged period [11], [12], [13]. Muscle weakness induced by this therapy can complicate parenteral short-term and high-dose use, especially in the case of chronic pathology. Corticosteroids have a direct catabolic effect on muscle, which lead to SKM atrophy. Moreover, muscle biopsies in patients receiving corticosteroids revealed nonspecific type 2 fiber atrophy (referred to as catabolic myopathy with type 2 fiber atrophy) [5, 6].

Alcohol-induced myopathies

Alcohol-induced myopathies have also been described in the literature, manifesting as acute necrotizing myopathy (with the process being usually segmental, involving few or many sarcomeres, but rarely the whole fiber), acute hypokalemic myopathy (which is associated with chronic alcoholism), and chronic alcoholic myopathy [6]. The development of acute alcohol-associated myopathy is typically associated with long-term alcoholism and occurs within a few hours following an intense episode of heavy drinking. The severity of the condition appears to be related to the amount of alcohol consumed, which may be why it is frequently seen during extended periods of alcohol consumption accompanied by fasting [14, 15]. In contrast, chronic alcohol-associated myopathy is characterized by a gradual onset of muscle weakness that primarily affects the proximal muscles over a period of several weeks to months. Diffuse SKM atrophy is common, and muscle biopsy reveals increased fat accumulation and type II fiber atrophy, which is similar to the changes seen in glucocorticoid-induced myopathy or disuse atrophy [16]. The prevalence of alcohol-induced myopathy is unknown.

Cocaine-induced myopathies

Cocaine may cause direct SKM damage due to its sympathomimetic activity; severe arterial vasoconstriction may cause SKM ischemia and infarction. Furthermore, direct cocaine-induced SKM injury may also occur due to cocaine-induced inhibition of catecholamines reuptake at alpha-adrenergic receptors, which may subsequently lead to high levels of intracellular calcium levels in myocytes and cell damage [17]. One study demonstrated that a minimum of 5 % of individuals who used cocaine and sought medical attention at an emergency department exhibited signs of SKM injury, as indicated by an increase in their CK levels [18].

Antimalarials-associated myopathies

Antimalarial therapy is widely used as a treatment for rheumatoid arthritis and systemic lupus erythematosus, and it has been linked with SKM injury in various reports [19]. In addition, the said drugs (chloroquine and hydroxychloroquine) (and therapeutics from other drug classes, e.g., amiodarone) have been associated with lysosomal/autophagic myopathies, where myeloid induction occurs (a generalized lysosomal storage disorder). Myopathy is a relatively rare adverse event associated with antimalarial drugs. Although there is no confirmation from other sources, a study conducted by Avina-Zubieta et al. [20] approximated the incidence to be one in every 100 patient-years.

Colchicine-induced myopathy

Colchicine, a popular drug for gout, has also been associated with SKM damage. It may cause direct toxicity to myocytes by inhibiting the polymerization of microtubules, subsequently disrupting the microtubule-dependent cytoskeletal network, which is responsible for conveying membranous organelles (such as lysosomes and autophagic vacuoles). This can later lead to the accumulation of these organelles, which has been seen in muscle biopsies (vacuolar myopathy with an accumulation of lysosomes and autophagic vacuoles without necrosis) [6, 21]. Unfortunately, there is a lack of information regarding the prevalence of colchicine-induced myopathies in the literature.

Immunologically-induced inflammatory myopathies

Numerous drugs may induce immune-mediated inflammatory myopathies, including anti-cancer therapeutics, statins, and penicillamine, amongst others.

As mentioned earlier, statins may cause direct toxicity to myocytes. However, they may also damage SKM by inducing necrotizing autoimmune myopathy (NAM). Statin-associated NAM has been well-documented in the literature, characterized clinically as an occurrence of subacute muscle weakness, severely increased creatine kinase (CK) levels (>×10 upper reference limit; URL), and the presence of circulating 3-hydroxy-3-methylglutaryl coenzyme A reductase (the pharmacological target of statin drugs) [5, 9]. Furthermore, statins may also induce polymyositis or dermatomyositis [5].

Penicillamine is another drug that has been associated with inflammatory myopathy, which has been said to resemble polymyositis both clinically and histologically [22]. It is used as a treatment for various disorders, including rheumatoid arthritis as well as Wilson’s disease. In cases of penicillamine-induced myopathy, biopsy usually shows perifascicular cellular infiltrates, as well as necrosis and regeneration of muscle fibers [23].

Cytokine therapies (interferon-alfa/beta, TNF-alpha blockers) are widely used as a treatment for various autoimmune diseases, carcinomas and chronic infections. However, one of the reported complications that have been associated with the said therapies is immune-mediated myopathy. Cases of both Type 1 interferon- and TNF-alfa/beta blocker-induced myositis have been presented in the past [24, 25].

Indirect skeletal muscle injury and other causes of rhabdomyolysis

Lastly, indirect SKM damage covers myopathies with a multifactorial etiology. This may include cases of drug-induced comas with subsequent ischemic muscle compression or drug-induced hypokalemia, amongst others [6].

Creatine supplementation has been linked with rhabdomyolysis in the past. However, this topic is greatly controversial. A recent review article conducted by Rawson et al. [26] thoroughly discussed this controversy. These authors concluded that creatine supplementation did not appear to be a precipitating factor for rhabdomyolysis. Interestingly, data from the literature has actually shown that creatine supplementation has a protective effect on muscle inflammation, damage, and injury in hard-training individuals [26].

Drug-induced skeletal muscle injury associated with anti-cancer treatment

Numerous groups of anti-cancer drugs have been associated with immune-mediated inflammatory myopathies, including immune checkpoint inhibitors (ICPIs), and monoclonal antibodies (e.g., bevacizumab), amongst others [5].

During the last decade, increasing reports have come out concerning SKM complications associated with the use of ICPIs, specifically programmed death-1 (PD-1) inhibitors [27]. The estimated incidence of this complication has been stated to range from 0.7 to 1.0 % [28]. Moreover, the clinical characteristics of these myopathies may have similarities with other immune-mediated myopathies, such as dermatomyositis [27]. However, atypical features such as oculo-bulbar impairment and co-existing myocarditis have been frequently reported [5]. The presence of multifocal clusters of necrotic fibers has also been considered a unique feature of ICPI-associated myopathy [27]. Shelly et al. [29] conducted a 5-year retrospective study of 24 patients with ICPI-associated myopathies (most of whom were taking pembrolizumab) and 38 patients with immune-mediated necrotizing myopathy (not exposed to ICPIs). In the study, they reported ocular involvement to be present in 9 out of 24 patients with ICPI exposure and in none of the immune-mediated necrotizing myopathy patients (p<0.001). Myocarditis was also present in eight patients with ICPI exposure and in none of the non-exposed subject groups (p<0.001). The occurrence of oculo-bulbar symptoms and myocarditis in patients receiving ICPIs has also been presented in other studies concerning PD-1 inhibitors (most commonly, pembrolizumab) [27, 30]. This further proves that these complications are quite specific to ICPIs. Furthermore, the occurrence of overlapping syndromes along with ICPI-associated myopathies, such as myasthenia gravis or neuropathic features, has been reported. The pathomechanism of SKM injury related to ICPI therapy is still poorly understood, unfortunately. However, it has been assumed that it can be associated with the induction of autoreactive T-cells and stimulation of autoantibody production as a result of the elimination of co-stimulatory molecule control over the immunological response [5].

Cases of SKM injury due to monoclonal antibodies, such as bevacizumab, sunitinib, and erlotinib, which are vascular endothelial growth factor (VEGF) inhibitors, have been reported in the literature [31, 32], albeit much less frequently than with ICPIs. Amongst the VEGF inhibitors, sunitinib seems to be the agent which is most frequently associated with SKM damage [31, 33]. The clinical and laboratory abnormalities in these cases seem to overlap, with patients demonstrating elevations in aminotransferases (AST/ALT) levels as well as very high values of creatine kinase (CK) [33]. However, as with ICPIs, the mechanism of myopathy with these drugs has not been investigated and is still not completely understood.

Chemotherapy is associated with several side effects, with cachexia (a multi-organ wasting syndrome), being the most prevalent (present in up to 80 % of cancer patients) [34]. SKM wasting and weakness are among the most characteristic symptoms in patients with cachexia. This may ultimately lead to lower tolerance to treatment and higher mortality rate in cancer patients [35, 36]. Three main pathways that contribute to SKM protein degradation have been presented: the lysosomal system, the cytosolic proteases, and the ubiquitin-proteosome pathway [37]. However, the ubiquitin-proteasome pathway seems to be responsible for the majority of SKM degradation in cancer cachexia, being stimulated by numerous cytokines, including tumor necrosis factor-alpha and interleukin-1 beta, amongst others [38].

Gemcitabine, a chemotherapeutic pyrimidine nucleoside prodrug, may cause SKM injury by a direct mechanism. These SKM side effects have been most frequently reported in patients co-treated with radiotherapy [39]. This occurrence has been referred to as «radiation recall», where the SKM and skin damage are mainly localized to previously irradiated areas [40]. However, cases of gemcitabine-induced acute myopathy in patients who have not been exposed to radiation have also been reported in the literature [41]. The mechanism of radiation recall has been described as a radiation-induced, continuous, and low-level release of the inflammation-mediating cytokines. The presence of a chemotherapy agent, such as gemcitabine, may subsequently upregulate these cytokines and lead to an inflammatory process [40].

Mitotic inhibitors, including vincristine, have also been associated with SKM injury [42, 43]. Vincristine is a chemotherapeutic agent that inhibits the formation of microtubules in the mitotic spindle, ultimately leading to an arrest of dividing cells at the metaphase stage. Hence, similarly to colchicine, vincristine may lead to microtubular myopathy [5].

Traditional and historical biomarkers of skeletal muscle injury

Laboratory diagnostic tests such as urine samples and blood tests are commonly used for diagnosing myopathies. Simple urinalysis is an important test for the diagnosis of possible SKM injury. The color of the urine in patients with rhabdomyolysis has been described as red/brown, tea-colored, and cola-colored [2]. Other additional signs that should be taken into consideration when using urinalysis for the diagnosis of SKM injury include the presence of proteins, density, and the pH of the urine [2]. A kaleidoscope of biomarkers of muscle injury have been proposed and analyzed (Table 2), with creatine kinase (CK) being the most popular in routine clinical practice. CK is an enzyme present in many organs and tissues, where it catalyzes the conversion of adenosine triphosphate and creatine to phosphocreatine and vice versa. Five isotypes of this enzyme exist in nature, three cytosolic (i.e., muscle-muscle CK [CK-MM], brain-brain [CK-BB], and muscle-brain [CK-MB]), and two mitochondrial (i.e., one ubiquitous [CK-Miu] and one sarcomeric [CK-Mis]) [44, 45]. In cases of SKM injury and rhabdomyolysis, elevated CK is said to be detectable within the first 24 h after the inciting SKM injury. The levels of CK peak around 72 h and return to baseline over a period of 7–12 days [46, 47]. Although CK is widely known as the main biomarker for diagnosing muscle tissue injury, it is not by any means perfect. Studies in the past have suggested ≥3–5× URL cut-offs as a diagnostic threshold for muscle injury [45, 48]. However, CK presents a high degree of inter-individual variability, which has been mainly demonstrated in individuals exhibiting a serum or plasma increase well above 5× URL after exercise [47]. Hence, there is still no universally agreed-upon range for normal CK values. Furthermore, there are numerous factors that may influence normal CK values in patients, such as sex, age, muscle mass, physical activity, renal function, and race. Males generally have a larger muscle mass, so their serum CK activities are higher compared to females [49]. Race has also been described as a relevant factor, with reports stating that the mean activity of CK in Black individuals is considerably higher than that in White individuals [50]. Notwithstanding, sustained exercise, such as in well-trained runners, increases the levels of the CK-MB isotype in SKM, which may produce abnormal serum CK-MB concentrations which may be confused with myocardial infarction [51].

Table 2:

The pathomechanisms and histological characteristics of drug-induced skeletal muscle myopathies.

General markers
Biomarker Sample type Approval Highlights Pros Cons
Creatine kinase (CK) Blood test Clinically approved
  1. Most popular biomarker for SKM damage

  2. Five isoenzymes consist in nature, with CK-MM being the most specific one for SKM

  3. The overall increase of levels in individuals with SKM damage may be up to 200-fold the URL

  1. CK substantially reflects the amount of injured muscle

  2. Low cost

  3. High availability

  4. High throughput

  1. Inter-individual variability

  2. Difficult to provide universal URL cut-offs

  3. Tissue distribution of CK activity varies in human muscles

  4. CK activity is said to depend on extracellular glutathione concentration

  5. CK is mainly metabolized by liver macrophages, so the plasma half-life of CK increases in severe liver disease

  6. Posttranscriptional CK modification

  7. Studies have shown that low CK values are associated with increased mortality-> poor quality as an injury marker

  8. Poor sensitivity for small/incomplete muscle injuries

Myoglobin (Myo)
  • Blood test

Urine test
Clinically approved
  1. Quite popular

  2. When over 100 g of muscle tissue is injured, Mb may build up in the kidney and cause acute kidney failure

  3. The overall increase of levels in individuals with SKM damage may be up to 50- to 100-fold the URL

  1. Increased levels of myoglobin reflect skeletal and heart muscle damage

  2. Moderate cost

  3. High availability

  4. High throughput

  5. Predicts renal injury

  1. Difficult to provide universal URL cut-offs

  2. Low sensitivity 24 h after injury and fast renal clearance from the circulation

  3. More expensive than the CK assay

  4. It is not possible to differentiate it from hemoglobin by strips when the first symptom is red urine

Lactate dehydrogenase (LDH) Blood test Clinically approved
  1. Serum LDH activity is a biomarker of cell damage

  2. Five isoenzymes exist in nature

  3. Kinetics are slower than CK, and Mb

  4. The overall increase of levels in individuals with SKM damage may be up to 20-fold the URL

  1. Increased levels observed after heavy muscular exercise associated with exertional rhabdomyolysis

  2. Low cost

  3. High availability

  4. High throughput

  1. Low specificity and sensitivity for SKM damage

Aspartate aminotransferase (AST) Blood test Clinically approved
  1. Present in numerous tissues

  2. Kinetics are slower than CK and Mb

  3. The overall increase of levels in individuals with SKM damage may be up to 10-fold the URL

  1. Increased levels are present as a result of SKM damage

  2. Low cost

  3. High availability

  4. High throughput

  1. Lower sensitivity and specificity for detecting SKM damage than CK

  2. No validated cutoffs for muscular injury

Novel/under investigation markers
Creatine kinase measured by mass assay and not activity assay (CKm) Research use only
  1. Analyzes the mass of the CK rather than its activity

  2. Target the CK-MM isoenzyme, but the antibodies utilized in the CKm assay also react with the CK-MB isoform

  1. Large fold-change increase from baseline concentrations compared to the CK activity→ enhanced dynamic range, improved sensitivity to detect changes in CK enzyme concentrations

  2. May detect SKM damage earlier than the general biomarkers

  1. Present in SKM and myocardial tissue as well as other organ tissues → may lower its sensitivity

    1. Relatively high cost

    2. Very low availability

  2. Issues with (external) quality control due to scarce usage in clinical labs

Fatty acid binding protein 3 (Fabp3) Research use only
  1. Is a cytosolic lipid transport protein

  2. Present in many tissues

  3. Similar kinetics (release, peaks, and clearance) to CK and AST activity assays-slightly earlier peak concentration when compared to the other biomarkers

  1. May detect SKM damage earlier than the general biomarkers

  1. Present in SKM and myocardial tissue as well as other organ tissues → may lower its sensitivity

    1. High cost

    2. Very low availability

  2. Issues with (external) quality control due to scarce usage in clinical labs

Myosin light chain 3 (Myl3) Research use only
  1. Is a component of myofilaments-found predominately in slow-twitch SKM and in cardiac muscle

  2. Similar kinetics (release, peaks, and clearance) to CK and AST activity assays-remained above baseline conc after 24 h

  1. May detect SKM damage earlier than the general biomarkers

  1. Present in SKM and myocardial tissue as well as other organ tissues → may lower its sensitivity

    1. High cost

    2. Very low availability

  2. Issues with (external) quality control due to scarce usage in clinical labs

Skeletal troponin I (sTnI) Research use only
  1. Is a component of myofilaments

  2. Can exist in two isoforms: slow-twitch (Type 1) or fast-twitch (Type II) SKM fibers

  3. Similar kinetics (release, peaks, and clearance) to CK and AST activity assays remained above baseline concentration after 24 h

  1. Skeletal muscle-specific protein biomarker

  2. High specificity

  3. May detect SKM damage earlier than the general biomarkers

  1. Not clinically validated

  2. No decision cutoffs

  3. High cost

  4. Very low availability

  5. Low throughput

  6. Challenging analytical technique

  7. No (external) quality control

microRNAs/myomiRs Research use only
  1. MyomiRs (miR) are microRNAs that are only expressed in muscle

  2. miR-1, miR-133a, and miR-206 are present in SKM and cardiac tissue

  3. miR-206 is only expressed in SKM

  1. High specificity

  2. High sensitivity

  3. Faster kinetics than CK

  1. High influence of preanalytical variables

  2. Not clinically validated

  3. High-interlaboratory variation

  4. No decision cutoffs

  5. High cost

  6. Very low availability

  7. Low throughput

  8. Challenging analytical technique

  9. No (external) quality control

  10. Normalization

Ultimately, this makes it extremely difficult to provide a universal URL cut-off value for CK in patients with SKM injury, which could have been incredibly useful clinically. The Common Terminology Criteria for Adverse Events (CTCAE) has provided a comprehensive grading system for adverse events used in all clinical trials, including a CK increase criteria grading system. It consists of four grades; Grade 1 consists of a CK value that is higher than the URL and lower than 2.5× the URL; Grade 2 represents a CK value between 2.5 and 5× the URL; Grade 3 portrays a CK value between 5 and 10× the URL; and lastly, Grade 4 represents CK values that are over 10× the URL.

During physical exertion and/or SKM injury (due to loss of membrane integrity of myocytes and/or their organelles, necrosis, etc.), CK and other intracellular proteins and enzymes, such as myoglobin (Myo) and aspartate transaminase (AST), are released into the bloodstream. Myo is a protein in the skeletal and cardiac muscles and is responsible for oxygen transport from the sarcolemma to the mitochondria [52]. It is a single polypeptide that consists of eight alfa-helices and contains a heme prosthetic group, which includes a porphyrin ring iron ion. Myo is rapidly excreted in the urine. After considerable SKM injury, the protein concentration markedly increases, reaches the peak between 1 and 3 days and returns to baseline after 2–4 days [45]. The rapid kinetics of Myo is one of its main limitations as a biomarker, along with its low specificity. When large quantities of Myo is present in the urine, it may produce visible changes in its color (red to brown), which has been reported in patients with rhabdomyolysis [53].

AST is, parallelly to CK and Myo, released from injured muscle tissue to the bloodstream and extracellular space. Its use in the diagnosis of muscle injury has been heavily debated. Previous prospective clinical studies have shown that there is an association between muscle injury and elevated aminotransferases [47, 54]. The same conclusions have also been presented in histological studies [55]. Acknowledging this relationship is of immense importance, both in clinical research and practice. When there is no clinical history of muscle disease or injury, physicians may automatically attribute elevated aminotransferases to liver injury. This may lead to unnecessary testing for liver disease (even occurring in patients with known rhabdomyolysis) [56]. However, reports have demonstrated that most of these additional tests come back negative, and 30–50 % of hepatobiliary imaging studies are normal, with most pathological findings being associated with hepatic steatosis [57]. The kinetics of AST have been shown to be much slower than that of CK and Myo. In rhabdomyolysis, a significant rise in AST is usually detectable at 24 h. Subsequently, it reaches its peak around 3–4 days post-injury. AST levels may return to baseline 6–10 days after heavy exercise [45], or, in cases of severe rhabdomyolysis, they may remain abnormal for 2–3 weeks [56]. Therefore, in cases where patients get late diagnosis of rhabdomyolysis/SKM injury, CK levels may have already normalized, while those of the aminotransferases may still be elevated. Unfortunately, AST is not suitable as an effective biomarker of SKM injury because, similarly to CK and Myo, it lacks tissue specificity and sensitivity [3, 58].

In patients with other serious comorbidities, such as in intensive care patients, the general markers (e.g., CK) have been described as ineffective markers of injury due to their instability [59]. Furthermore, numerous tumors, especially epithelial cancers (e.g., breast and prostate tumors), express Myo [60]. Therefore, in theory, in the event of cell injury and death (or in the case of effective anti-cancer therapy), the Myo could leak into the serum and affect its concentration levels. Furthermore, elevated levels of CK-BB in the serum have also been associated with the presence of possible malignancy [61].

Historical and non-traditional biomarkers for both exertional and drug-induced SKM injury have been proposed in the past. These mainly include aldolase (Ald), lactate dehydrogenase (LDH), and carbonic anhydrase III (CA III). Ald is a glycolytic enzyme that catalyzes the conversion of fructose 1-6-bisphosphate in glyceraldehyde 3-phosphate and dihydroxyacetone phosphate. It is present in various tissues, including SKM, liver, and brain, thus lowering its specificity as a biomarker of SKM injury [45]. Other studies in the past have shown that Ald has slow kinetics compared to the other general biomarkers, displaying a significant increase over the URL only 48 h after SKM damage [62]. LDH is also released in response to SKM injury, reaching up to >10× the URL in cases of significant SKM damage [45]. However, the kinetics of this biomarker are much slower than that of CK and Myo, making it less sensitive for detecting injury to the SKM. CA III has also been analyzed in the past. The said enzyme catalyzes the rapid conversion of carbon hydroxide and water to bicarbonate and hydrogen. CA III is an isoform of the carbonic anhydrases and is mainly located in SKM (predominately in Type I, slow twitch fibers) [63]. However, similarly to Ald, CA III is also located in various other tissues, including cardiac and smooth muscle, adipocytes and liver, thereby reducing its diagnostic specificity as a biomarker for SKM injury. However, contrary to Ald, the kinetics of CA III is more rapid and similar to that of Myo [64].

Novel translational biomarkers of skeletal muscle injury

There is undoubtedly a need for specific, sensitive, and qualified biomarkers that may effectively help diagnosing SKM injury. Luckily, new promising biomarkers and platforms have recently been evaluated [3]. The Critical Path Institute’s (C-path) Predictive Safety Testing Consortium (PSTC) conducts thorough analysis and qualifies translational biomarkers for the FDA, which can then be used in clinical trials. Recently, they have evaluated a «novel» immunoassay-based muscle injury biomarker panel (MIP), that includes new potential biomarkers for the detection of SKM injury. These include fatty acid binding protein 3 (Fabp3), which is highly abundant in skeletal muscle, and skeletal troponin I (sTnI), which is strictly restricted to skeletal muscle, making it extremely specific, myosin light chain 3 (Myl3), fatty acid-binding protein 3 (FABP3), and CK measured by mass assay (CKm) [65]. The said biomarkers are now being analyzed in non-human primate-based studies. Vlasakova et al. [65] conducted a study concerning the response of these novel SKM biomarkers in dogs to drug-induced SKM injury and sustained endurance exercise. In both dog models, the novel biomarkers outperformed the general ones (CK activity assay and AST), showing higher specificity and sensitivity. In both dog models, the novel biomarkers reached much higher concentration peaks than the general ones. The same conclusions were reached in a study conducted by Burch et al. [66], where the performance of these novel biomarkers was evaluated in drug-induced SKM injury in rats. Overall, the potential of this novel MIP is incredibly high. The said biomarkers and platforms which are under investigation have demonstrated an enhanced dynamic range and improved sensitivity to detect SKM injury [3]. This may be incredibly useful in clinical research due to their ability to provide enhanced laboratory monitoring of patients in early-phase clinical trials, for which the only data has been derived from pre-clinical investigations. This can aid in establishing direct relationships between drug concentrations and the extent of muscle injury, which can ultimately ensure patient safety.

A few words about cardiac troponins

There has been open debate in the past about the fact that cardiac troponins I (cTnI) and T (cTnT) may be elevated in the course of SKM injury due to potential ectopic production in the skeletal muscle, thus lowering their specificity for diangosing cardiac injury. After garnering a vast amount of biological and clinical information, such hypothesis has been definitely ruled out. As recently emphasized by Giannitsis et al. [67]. First, the possible re-expression of cardiac troponins in chronically injuried and/or regenerating SKM is not scientifically proven. Then, even if all cardiac troponin assays could at least in theory display a certain degree of cross-reactivity with SKM isoforms, this eventuality has been almost ruled out with currently available commercially tests. Finally, the most obvious reason for obtaining increased cardiac troponin levels in patients with chronic SKM injury (e.g., muscular dystrophies), is certainly cardiac involvement, even at a subclinical extent.

Approach to monitoring drug-induced injury to skeletal muscle

Having a systematic algorithm for monitoring drug-induced injury to the SKM would be immensely useful in both medical practices, as well as in clinical trials. Therefore, we would like to propose a novel approach for monitoring drug-induced injury to the muscle (Figure 1). First, the baseline risk of SKM injury of the employed drug(s)/therapeutic regimen should be assessed. In early phase trials, this may be based only on preclinical data or data derived from similar class agents. The CK values should be measured at baseline, during routine assessments (i.e. start of each new therapy cycle), or as otherwise clinically indicated (out-of-window). Specific testing for CK ought to be performed in case of the presence of characteristic signs and symptoms associated with myopathies (muscle pain, weakness, dark urine). CK should also be measured in the presence of elevated creatinine while on treatment to rule out a muscular etiology. However, when analyzing the value of measured CK, it is extremely important to take into consideration the dynamics of this enzyme (kinetics, half-life, individual variability, etc.). Our recommended criteria for further investigation of potential drug-induced SKM injury (i.e., classifying CK as elevated) is based on the Common Terminology Criteria for Adverse Events (CTCAE) grading system: CTCAE grade ≥1 criteria (ULN – 2.5× ULN) if symptomatic or CTCAE grade ≥2 (2.5–5× ULN) if asymptomatic. This accounts for some variability in baseline and clinically nonsignificant fluctuations. If the CTCAE based criteria is reached, further testing to confirm a diagnosis of SKM injury should be performed (using the secondary general markers, i.e., Myo, CK-MM, CK-MB, AST). Subsequently, if the signal of SKM injury is confirmed, it is crucial to rule out other potential causes of elevation in these biomarkers, including liver injury (by assessing ALT and bilirubin) and cardiac disorders (by assessing levels cTnI or cTnT), as well as monitoring biomarkers of AKI (serum creatinine, blood urea nitrogen, etc.) due to the potential rhabdomyolysis or subaucte kidney injury.

Figure 1: 
Proposed algorithm for monitoring drug-induced skeletal muscle injury. *In the event of negative dechallenge, a rechallenge procedure may still be implemented. SKM, skeletal muscle; CK, creatine kinase; ULN, upper limit of normal; Myo, myoglobin; AST, aspartate transaminase; SCr, serum creatinine; BUN, blood urea nitrogen; ALT, alanine transaminase; Fabp3, fatty acid-binding protein 3; Myl3, myosin light chain 3; sTnI, skeletal troponin I.
Figure 1:

Proposed algorithm for monitoring drug-induced skeletal muscle injury. *In the event of negative dechallenge, a rechallenge procedure may still be implemented. SKM, skeletal muscle; CK, creatine kinase; ULN, upper limit of normal; Myo, myoglobin; AST, aspartate transaminase; SCr, serum creatinine; BUN, blood urea nitrogen; ALT, alanine transaminase; Fabp3, fatty acid-binding protein 3; Myl3, myosin light chain 3; sTnI, skeletal troponin I.

The frequency of testing in this algorithm should be based on the overall risk of SKM damage induced by the employed drug(s)/therapeutic regimen and/or clinically guided by overall symptomatology. In general, early-phase clinical trials, assessments should be done at minimum monthly, at the beginning of each cycle. During the first cycle, testing should be performed multiple times. In later phase studies, careful monitoring should continue to be performed at frequent intervals given that some side effects may not be identified until a drug is administered in larger more diverse populations. In clinical practice, we recommend routine assessments based on overall risk, with CK measured as part of routine laboratory assessments of patients. Given the potential for variability in CK, baseline measures should be obtained prior to initiation of any new therapy. Finally, given the potential for immune-mediated mechanisms of drug-induced SKM injury which may not appear till late, we recommend employing a safety follow up assessment window of 90 days post-discontinuation of any immunotherapy.

Biomarker–guided challenge–dechallenge–rechallenge algorithm for skeletal muscle injury

In both clinical practie and drug trials, challenge–dechallenge–rechallenge is a strategy in which a drug (or combination of drugs) is administered, withdrawn, then re-administered, while the presence of adverse event(s) is carefully monitored and tracked. Figure 1 incorporates a procedure in which an employed drug/therapeutic regimen becomes dechallenged and rechallenged using CK to guide the process. This may ultimately help to guide clinicians to confirm or deny if the drug in question is the possible cause of the SKM damage. In the proposed algorithm, we again employed the same CTCAE criteria used in the safety monitoring strategy to account for inter-patient variability in CK levels. If the signal of SKM injury is confirmed via assessment of additional biomarkers, a de-challenge can be performed (i.e. temporarily stopping therapy or reducing dose) to determine if elevated CK/clinical symptoms persist (negative dechallenge, indicative of alternative etiology) or decrease/disappear (positive dechallnege, potentially indicative of a drug-induced etiology). If a positive dechallenge is observed as indicated by resolving symptoms or CK decrease, a rechallnege can be performed by which the drug(s) is restarted (at full or reduce dose or in full or partial combination) under careful monitoring by the treating physician. If rechallenge is confirmed to be positive as indicated by reappearing symptoms or new CK elevation, a drug-induced myopathy can be highly suspected and appropriate action taken based on the overall clinical status including reducing the dose of offending agent or, if considered severe, stopping the therapeutic regiment for an alternative treatment. In practice, the results of dechallenge–rechallenge are often unclear and require consideration of broad number of clinical variables, often painting a complex clinical picture. This is magnified in early-phase oncology, in which patients may already be quite sick at enrollment and/or suffer from multiple co-morbidities. Finally, in cases of combination trials, especially with ICPIs that have a known risk for SKM injury, dechallenge–rechallenge cycles may need to be repeated, removing different agents and/or dose alterations of different agents, in order to identify the offending agent and/or a toxicity potentiating effect/drug–drug interactions.

Summary and conclusions

Drug-induced myopathy is challenging condition to identify and diagnosis due to unspecific, often vague clinical symptoms. While it is clear that the available biomarkers for SKM injury, due to inadequate sensitivity and specificity, do not fully meet the needs for satisfactory detection of drug-induced damage both in clinical and research settings, we present here a biomarker-guided approach, incorporating several biologic, clinical, and logistic factors, to aid in establishing a diagnosis of SKM injury and exploring a drug-induced etiology, with the goal to enable timely and appropriate intervention. This proposed algorithm for safety monitoring of drug-induced SKM injury may have significant utility in both medical practice and clinical trials and improve patient safety and outcomes.

Corresponding author: Brandon M. Henry, MD, Clinical Laboratory, Division of Nephrology and Hypertension Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA; and Cmed Research Inc., Morrisville, NC, USA, Phone/Fax: +1 513 636 4200, E-mail:

  1. Research funding: None declared.

  2. Author contributions: All the authors have accepted responsibility for the entire content of this submitted manuscript and approved submission.

  3. Competing interests: BMH and AEA are employees of Cmed Research Inc. All other authors state no conflict of interest.

  4. Informed consent: Not applicable.

  5. Ethical approval: Not applicable.


1. Prendergast, BD, George, CF. Drug-induced rhabdomyolysis–mechanisms and management. Postgrad Med J 1993;69:333–6. in Google Scholar PubMed PubMed Central

2. Cervellin, G, Comelli, I, Benatti, M, Sanchis-Gomar, F, Bassi, A, Lippi, G. Non-traumatic rhabdomyolysis: background, laboratory features, and acute clinical management. Clin Biochem 2017;50:656–62. in Google Scholar PubMed

3. Goldstein, RA. Skeletal muscle injury biomarkers: assay qualification efforts and translation to the clinic. Toxicol Pathol 2017;45:943–51. in Google Scholar PubMed

4. Ferrara, R, Pilotto, S, Caccese, M, Grizzi, G, Sperduti, I, Giannarelli, D, et al.. Do immune checkpoint inhibitors need new studies methodology? J Thorac Dis 2018;10:S1564–80. in Google Scholar PubMed PubMed Central

5. Mastaglia, FL. The changing spectrum of drug-induced myopathies. Acta Myol 2020;39:283–8. in Google Scholar PubMed PubMed Central

6. Sieb, JP, Gillessen, T. Iatrogenic and toxic myopathies. Muscle Nerve 2003;27:142–56. in Google Scholar PubMed

7. Kumar, S, Anne, S, B, HK. Statin induced rhabdomyolysis. J Assoc Physicians India 2021;69:11–2.Search in Google Scholar

8. Waclawik, AJ, Lindal, S, Engel, AG. Experimental lovastatin myopathy. J Neuropathol Exp Neurol 1993;52:542–9. in Google Scholar PubMed

9. Mammen, AL. Statin-associated autoimmune myopathy. N Engl J Med 2016;374:664–9. in Google Scholar PubMed

10. Pereira, RMR, Freire de Carvalho, J. Glucocorticoid-induced myopathy. Joint Bone Spine 2011;78:41–4. in Google Scholar PubMed

11. Surmachevska, N, Tiwari, V. Corticosteroid induced myopathy. Treasure Island (FL): StatPearls Publishing; 2023.Search in Google Scholar

12. Dirks-Naylor, AJ, Griffiths, CL. Glucocorticoid-induced apoptosis and cellular mechanisms of myopathy. J Steroid Biochem Mol Biol 2009;117:1–7. in Google Scholar PubMed

13. Gupta, A, Gupta, Y. Glucocorticoid-induced myopathy: pathophysiology, diagnosis, and treatment. Indian J Endocrinol Metab 2013;17:913. in Google Scholar PubMed PubMed Central

14. Martin, F, Ward, K, Slavin, G, Levi, J, Peters, TJ. Alcoholic skeletal myopathy, a clinical and pathological study. Q J Med 1985;55:233–51.Search in Google Scholar

15. Haller, RG, Knochel, JP. Skeletal muscle disease in alcoholism. Med Clin 1984;68:91–103. in Google Scholar

16. Lafair, JS. Alcoholic myopathy. Arch Intern Med 1968;122:417. in Google Scholar

17. Parks, JM, Reed, G, Knochel, JP. Case report: cocaine-associated rhabdomyolysis. Am J Med Sci 1989;297:334–6. in Google Scholar PubMed

18. Brody, SL, Wrenn, KD, Wilber, MM, Slovis, CM. Predicting the severity of cocaine-associated rhabdomyolysis. Ann Emerg Med 1990;19:1137–43. in Google Scholar PubMed

19. Naddaf, E, Paul, P, AbouEzzeddine, OF. Chloroquine and hydroxychloroquine myopathy: clinical spectrum and treatment outcomes. Front Neurol 2021;11:1–10. in Google Scholar PubMed PubMed Central

20. Avtna-Zubieta, JA, Johnson, ES, Suarez-Almazor, ME, Russell, AS. Incidence of myopathy in patients treated with antimalarials. A report of three cases and a review of the literature. Rheumatology 1995;34:166–70. in Google Scholar PubMed

21. Kuncl, RW, Duncan, G, Watson, D, Alderson, K, Rogawski, MA, Peper, M. Colchicine myopathy and neuropathy. N Engl J Med 1987;316:1562–8. in Google Scholar PubMed

22. Carroll, GJ, Will, RK, Peter, JB, Garlepp, MJ, Dawkins, RL. Penicillamine induced polymyositis and dermatomyositis. J Rheumatol 1987;14:995–1001.10.1007/978-94-010-9775-8_31Search in Google Scholar

23. Halla, JT, Fallahi, S, Koopman, WJ. Penicillamine-induced myositis. Am J Med 1984;77:719–22. in Google Scholar PubMed

24. Somani, AK, Swick, AR, Cooper, KD, McCormick, TS. Severe dermatomyositis triggered by interferon beta-1a therapy and associated with enhanced type I interferon signaling. Arch Dermatol 2008;144:1341–9. in Google Scholar PubMed PubMed Central

25. Zengin, O, Onder, ME, Alkan, S, Kimyon, G, Hüseynova, N, Demir, ZH, et al.. Three cases of anti-TNF induced myositis and literature review. Rev Bras Reumatol 2017;57:590–5. in Google Scholar PubMed

26. Rawson, ES, Clarkson, PM, Tarnopolsky, MA. Perspectives on exertional rhabdomyolysis. Sports Med 2017;47:33–49. in Google Scholar PubMed PubMed Central

27. Liewluck, T, Kao, JC, Mauermann, ML. PD-1 inhibitor-associated myopathies: emerging immune-mediated myopathies. J Immunother 2018;41:208–11. in Google Scholar PubMed

28. Albarrán-Artahona, V, Laguna, J-C, Gorría, T, Torres-Jiménez, J, Pascal, M, Mezquita, L. Immune-related uncommon adverse events in patients with cancer treated with immunotherapy. Diagnostics 2022;12:2091. in Google Scholar PubMed PubMed Central

29. Shelly, S, Triplett, JD, Pinto, MV, Milone, M, Diehn, FE, Zekeridou, A, et al.. Immune checkpoint inhibitor-associated myopathy: a clinicoseropathologically distinct myopathy. Brain Commun 2020;2:1–16. in Google Scholar PubMed PubMed Central

30. Tomoaia, R, Beyer, RȘ, Pop, D, Minciună, IA, Dădârlat-Pop, A. Fatal association of fulminant myocarditis and rhabdomyolysis after immune checkpoint blockade. Eur J Cancer 2020;132:224–7. in Google Scholar PubMed

31. Ruggeri, EM, Cecere, FL, Moscetti, L, Doni, L, Padalino, D, Di Costanzo, F. Severe rhabdomyolysis during sunitinib treatment of metastatic renal cell carcinoma. A report of two cases. Ann Oncol 2010;21:1926–7. in Google Scholar PubMed

32. Hugo Javier, Madariaga Charaja, Valery, Ascuña. Abstracts, 21st PANLAR meeting. J Clin Rheumatol 2019;25:S1-96. in Google Scholar

33. Liman, AD, Passero, VA, Liman, AK, Shields, J. A rare case of sunitinib-induced rhabdomyolysis in renal cell carcinoma. Case Rep Oncol Med 2018;2018:1–4. in Google Scholar PubMed PubMed Central

34. Huot, JR, Pin, F, Bonetto, A. Muscle weakness caused by cancer and chemotherapy is associated with loss of motor unit connectivity. Am J Cancer Res 2021;11:2990–3001.Search in Google Scholar

35. Dewys, WD, Begg, C, Lavin, PT, Band, PR, Bennett, JM, Bertino, JR, et al.. Prognostic effect of weight loss prior tochemotherapy in cancer patients. Am J Med 1980;69:491–7. in Google Scholar

36. von Haehling, S, Anker, SD. Prevalence, incidence and clinical impact of cachexia: facts and numbers-update 2014. J Cachexia Sarcopenia Muscle 2014;5:261–3. in Google Scholar PubMed PubMed Central

37. Melstrom, LG, Melstrom, KA, Ding, XZ, Adrian, TE. Mechanisms of skeletal muscle degradation and its therapy in cancer cachexia. Histol Histopathol 2007;22:805–14. in Google Scholar PubMed

38. Lecker, SH, Solomon, V, Mitch, WE, Goldberg, AL. Muscle protein breakdown and the critical role of the ubiquitin-proteasome pathway in normal and disease states. J Nutr 1999;129:227S–37S. in Google Scholar PubMed

39. Spielmann, L, Messer, L, Moreau, P, Etienne, E, Meyer, C, Sibilia, J, et al.. Gemcitabine-induced myopathy. Semin Arthritis Rheum 2014;43:784–91. in Google Scholar PubMed

40. Burris, HA, Hurtig, J. Radiation recall with anticancer agents. Oncologist 2010;15:1227–37. in Google Scholar PubMed PubMed Central

41. Ardavanis, AS, Ioannidis, GN, Rigatos, GA. Acute myopathy in a patient with lung adenocarcinoma treated with gemcitabine and docetaxel. Anticancer Res 2005;25:523–5.Search in Google Scholar

42. Deangelis, LM, Gnecco, C, Taylor, L, Warrell, RP. Evolution of neuropathy and myopathy during intensive vincristine/corticosteroid chemotherapy for non-Hodgkin’s lymphoma. Cancer 1991;67:2241–6.<2241::AID-CNCR2820670905>3.0.CO;2-A.10.1002/1097-0142(19910501)67:9<2241::AID-CNCR2820670905>3.0.CO;2-ASearch in Google Scholar

43. Le Quintrec, JS, Le Quintrec, JL. Drug-induced myopathies. Baillieres Clin Rheumatol 1991;5:21–38. in Google Scholar

44. McLeish, MJ, Kenyon, GL. Relating structure to mechanism in creatine kinase. Crit Rev Biochem Mol Biol 2005;40:1–20. in Google Scholar

45. Lippi, G, Schena, F, Ceriotti, F. Diagnostic biomarkers of muscle injury and exertional rhabdomyolysis. Clin Chem Lab Med 2018;57:175–82. in Google Scholar

46. Paidoussis, D. Severe rhabdomyolysis associated with a popular high-intensity at-home exercise program. J Med Cases 2012;4:12–4. in Google Scholar

47. Pettersson, J, Hindorf, U, Persson, P, Bengtsson, T, Malmqvist, U, Werkström, V, et al.. Muscular exercise can cause highly pathological liver function tests in healthy men. Br J Clin Pharmacol 2008;65:253–9. in Google Scholar PubMed PubMed Central

48. Tietze, DC, Borchers, J. Exertional rhabdomyolysis in the athlete. Sport Health: A Multidiscip Approach 2014;6:336–9. in Google Scholar PubMed PubMed Central

49. Aujla, RS, Patel, R. Creatine phosphokinase. Treasure Island (FL): StatPearls Publishing; 2023.Search in Google Scholar

50. Brewster, LM, Mairuhu, G, Sturk, A, van Montfrans, GA. Distribution of creatine kinase in the general population: implications for statin therapy. Am Heart J 2007;154:655–61. in Google Scholar PubMed

51. Lippi, G, Banfi, G. Distribution of creatine kinase in sedentary and physically active individuals. Am Heart J 2008;155:e51. in Google Scholar PubMed

52. Gros, G, Wittenberg, BA, Jue, T. Myoglobin’s old and new clothes: from molecular structure to function in living cells. J Exp Biol 2010;213:2713–25. in Google Scholar PubMed PubMed Central

53. Gabow, PA, Kaehny, WD, Kelleher, SP. The spectrum of rhabdomyolysis. Medicine 1982;61:141–52. in Google Scholar PubMed

54. Pal, S, Chaki, B, Chattopadhyay, S, Bandyopadhyay, A. High-intensity exercise induced oxidative stress and skeletal muscle damage in postpubertal boys and girls: a comparative study. J Strength Condit Res 2018;32:1045–52. in Google Scholar PubMed

55. Apple, FS. Serum and muscle alanine aminotransferase activities in marathon runners. JAMA, J Am Med Assoc 1984;252:626. in Google Scholar PubMed

56. Lim, AK. Abnormal liver function tests associated with severe rhabdomyolysis. World J Gastroenterol 2020;26:1020–8. in Google Scholar PubMed PubMed Central

57. Lim, AKH, Arumugananthan, C, Lau, H, Yim, C, Jellie, LJ, Wong, EWW, et al.. A cross-sectional study of the relationship between serum creatine kinase and liver biochemistry in patients with rhabdomyolysis. J Clin Med 2019;9:81. in Google Scholar PubMed PubMed Central

58. Castro, C, Gourley, M. Diagnosis and treatment of inflammatory myopathy: issues and management. Ther Adv Musculoskelet Dis 2012;4:111–20. in Google Scholar PubMed PubMed Central

59. Delanghe, JR, Speeckaert, MM, De Buyzere, ML. Is creatine kinase an ideal biomarker in rhabdomyolysis? Reply to Lippi et al.: diagnostic biomarkers of muscle injury and exertional rhabdomyolysis ( Clin Chem Lab Med 2019;57:e75–6. in Google Scholar PubMed

60. Bicker, A, Nauth, T, Gerst, D, Aboouf, M, Fandrey, J, Kristiansen, G, et al.. The role of myoglobin in epithelial cancers: insights from transcriptomics. Int J Mol Med 2019;45:385–400. in Google Scholar PubMed PubMed Central

61. Silverman, LM, Dermer, GB, Zweig, MH, Van Steirteghem, AC, Tökés, ZA. Creatine kinase BB: a new tumor-associated marker. Clin Chem 1979;25:1432–5. in Google Scholar

62. Sietsema, KE, Meng, F, Yates, NA, Hendrickson, RC, Liaw, A, Song, Q, et al.. Potential biomarkers of muscle injury after eccentric exercise. Biomarkers 2010;15:249–58. in Google Scholar PubMed

63. Harju, AK, Bootorabi, F, Kuuslahti, M, Supuran, CT, Parkkila, S. Carbonic anhydrase III: a neglected isozyme is stepping into the limelight. J Enzym Inhib Med Chem 2013;28:231–9. in Google Scholar PubMed

64. Beuerle, JR, Azzazy, HM, Styba, G, Duh, SH, Christenson, RH. Characteristics of myoglobin, carbonic anhydrase III and the myoglobin/carbonic anhydrase III ratio in trauma, exercise, and myocardial infarction patients. Clin Chim Acta 2000;294:115–28. in Google Scholar PubMed

65. Vlasakova, K, Lane, P, Michna, L, Muniappa, N, Sistare, FD, Glaab, WE. Response of novel skeletal muscle biomarkers in dogs to drug-induced skeletal muscle injury or sustained endurance exercise. Toxicol Sci 2017;156:kfw262. in Google Scholar PubMed

66. Burch, PM, Greg Hall, D, Walker, EG, Bracken, W, Giovanelli, R, Goldstein, R, et al.. Evaluation of the relative performance of drug-induced skeletal muscle injury biomarkers in rats. Toxicol Sci 2016;150:247–56. in Google Scholar PubMed

67. Giannitsis, E, Mueller, C, Katus, HA. Skeletal myopathies as a non-cardiac cause of elevations of cardiac troponin concentrations. Diagnosis 2019;6:189–201. in Google Scholar PubMed

Received: 2023-03-27
Accepted: 2023-04-28
Published Online: 2023-05-16
Published in Print: 2023-09-26

© 2023 Walter de Gruyter GmbH, Berlin/Boston

Downloaded on 30.11.2023 from
Scroll to top button