Targeting Skeletal Muscle Dysfunction With L-Carnitine for the Treatment of Patients With Chronic Obstructive Pulmonary Disease

Abstract

Chronic obstructive pulmonary disease (COPD) is a major medical problem and the world’s third leading cause of death. COPD is a chronic disease with heterogeneous clinical symptoms, disease progression, and treatment responses. Besides pulmonary symptomatology, the common systemic clinical manifestations are cachexia, muscle weakness, and widespread comorbidities such as cardiovascular diseases, diabetes, osteoporosis, and infections. The adverse effects of pharmaceutical therapies contribute to the difficulty of health risk assessment and management of COPD patients. This review shows how skeletal muscle dysfunction and metabolic abnormalities contribute significantly to COPD patients’ symptoms, functional activities, quality of life, and overall disease outcomes. Based on the clinical evidence of L-carnitine and derivatives as metabolic and muscle bioenergetic enhancers, we propose broader research and implementation of this nutraceutical agent as an effective, inexpensive, and safe adjuvant therapeutic for the long-term management of COPD patients. Moreover, we believe the management of COPD as a chronic disease should be shifted from symptomatic reactive pharmaceutical intervention to more constructive and non-toxic approaches using a single or combination of natural and nutritional agents with potential muscle metabolic enhancing and immunomodulating activities to achieve a better overall outcome for the patients in terms of morbidity, mortality, and medical cost-reduction.

Chronic obstructive pulmonary disease (COPD) is a severe medical problem predicted to worsen in the coming years. It is the third leading cause of death globally (1). In Asia-Pacific territories, where the issue has been historically underdiagnosed and under-reported, patients with COPD were estimated to be 6.2%, while 19.1% of these patients presented with a severe type of disease (2). Dyspnea and productive cough are the common manifestations found in patients with COPD. Patients with exacerbations of COPD may lead to a mortality rate of 10% of hospitalized cases (3). Besides respiratory exacerbations, other systemic manifestations of COPD may cause mortality in these patients, including cachexia and muscle weakness. Other comorbidities, such as cardiovascular disease, diabetes, infections, and side effects of anti-inflammatory drugs, may contribute to the deterioration of patients’ functional capabilities, quality of life, and early death (4). It has become clear that symptoms of COPD are not only of the respiratory system but of many other organs and systems combined, including the musculoskeletal system (5), circulatory system, cardiac system (6), immune system (7), bone metabolism (8), and others (9).

COPD patients exhibit significant skeletal muscle dysfunction, a primary pathology associated with a sedentary lifestyle and decreased survival rate. Muscle weakness occurs because of functional, metabolic, and histological abnormalities (10). It affects both respiratory and extremity muscles but is typically more severe in limb muscles. Lower limb dysfunction, especially the weakening of quadriceps muscle strength, is more commonly observed due to inflammation, hypoxia, and nutritional depletion and has been linked to the severity of COPD progression (11), reduced patient functional activities, increased hospitalization rates, and increased mortality (12,13). In addition to limb muscle dysfunction, respiratory muscle dysfunction is associated with specific conventional treatments to alleviate and improve symptoms (14). The foundation of treatment for muscle dysfunction in COPD is graded exercise therapy and adequate nutrition (15,16).

L-carnitine (beta-hydroxy-gamma N-trimethyl amino-butyric acid) is a quaternary amine that serves as an essential transporting cofactor that delivers fatty acids into the mitochondrial matrix and plays a critical role in the metabolism of fatty acids. It was first discovered as a component of muscle in 1905 (15,16). L-carnitine decreases oxidative stress and inflammation by modulating efficient fatty acid oxidation (17). These functions can reduce cytokine production of the inflammatory process and decrease myocyte damage in patients and athletes during extensive exercises. L-carnitine can be endogenously synthesized from lysine and methionine (18) or absorbed via the gastrointestinal tract through the consumption of animal-based food products. Supplementation of L-carnitine and amino acid-sparing exercises have been reported to allow more amino acids to potentially be available for new protein synthesis while increasing strength and endurance, suggesting the use of L-carnitine to improve recovery after exercise and increase muscle mass during endurance exercise (19).

Drastic reduction in muscle strength and endurance characterizes muscle dysfunction in COPD patients. Numerous factors distribute to the pathogenesis of muscle dysfunction, including low physical activities, malnutrition, smoking, aging, systemic inflammation, corticosteroid usage, hypoxemia, and increased myofibrillar protein degradation (19). Therefore, choosing an inexpensive nutritional supplement to reduce the burden of many musculoskeletal dysfunctions can be the key to alleviating COPD symptoms. This current review analyzes the energetic metabolic impairment in the pathogenesis of muscle dysfunction in COPD patients. Based on the impressive clinical efficacy of L-carnitine and derivatives in a variety of acute and chronic pathologies, we substantiate the rationale for broader research in the application of this nutraceutical agent to correct muscle metabolic derangement (structural and functional alterations) with potential therapeutic benefits in improving quality of life, morbidity, and mortality of patients with COPD.

Skeletal Muscle Dysfunction in COPD Patients

Patients with COPD often show alteration in their skeletal structure (fiber size and distribution, capillary density, and metabolic balance) and muscle function (strength and endurance) (10). Loss of muscle mass was found in approximately 30-40% of these patients; however, weight is often unchanged since fat mass is relatively maintained (20). Muscle atrophy associated with COPD has been confirmed with multiple imaging studies, including magnetic resonance imaging (MRI) (21), computed tomography (CT) (22), and ultrasound (23), showing that muscle atrophy occurs throughout the whole body.

Impairment in muscle strength in COPD patients predominantly involves the lower extremity muscles (24). In moderate to severe COPD patients, quadriceps femoris muscle strengths are 20% to 30% lower compared to healthy subjects (25). Quadriceps maximal voluntary contraction force (QMVC) was used to measure the degree of limb muscle strength correlated with the severity of the COPD course. In a prospective study, Hopkinson et al. (26) showed that the mean QMVC in COPD patients declined by 4.3% over a year compared to 1-2% in a healthy aging population (27). Reducing muscle weakness and physical exertion ability leads to disabilities in COPD patients, corresponding to increased health care resource utilization. The study from Montes de Oca M et al. (28) exhibits the significant contribution of quadriceps femoris muscle strength to a higher cost of medical care and mortality in COPD patients. Skeletal muscle dysfunction also leads to poor healthcare outcomes in stable COPD patients (10). Moreover, it has been reported that reduced extremity muscle strength in moderate COPD cases contributes to increased dyspnea, poor physical functioning, and declining quality of life (29). Low limb muscle strength is a reliable indicator of mortality in patients with severe COPD (13).

Several published studies demonstrated that patients with moderate COPD lose about 30% of their limb muscle endurance. This reduction is strongly correlated with worsening activity index, such as forced expiratory volume in one second (FEV₁) and resting partial pressure of oxygen in arterial blood (PaO₂) (30). Notably, muscle endurance is related to muscle oxidative capacities (31). There is a positive correlation observed between thigh circumference and the proportion of type I muscle fibers and citrate synthase activity (31). Therefore, the higher reliance of the muscles on anaerobic glycolysis leads to lactate buildup as a metabolic byproduct, contributing to premature muscle fatigue (32). Due to the lack of peripheral muscle endurance, there is a greater propensity for these patients to deteriorate even further from the limitations of exercises these patients can perform (33).

Evidence of Metabolic Impairments in COPD Patients’ Skeletal Muscles

Skeletal muscle metabolism in COPD patients has been documented with intrinsic abnormalities. Contractile fatigue is a significant issue demonstrated in the muscle fibers of patients with COPD (34). Within 30 minutes after exercising, the quadriceps twitch force substantially decreased by more than 20% in severe COPD patients. In addition, the likelihood of developing quadriceps fatigue in exhaustive cycle exercise in COPD patients is greater than that in age-matched healthy controls (35).

In patients with severe COPD, the fiber-type ratios in the quadriceps femoris muscles were redistributed, decreased in the proportion of slow-twitch oxidative type I fibers, and increased in the proportion of fast-twitch glycolytic type IIb fibers (36). A subsequent study confirmed this redistribution within the vastus lateralis muscles in severe COPD patients (37). In another study, the authors reported that patients with COPD have 20% less proportion of type I fibers but 10% more type IIb fibers proportion (38). In a systemic review, the FEV₁, FEV₁/forced vital capacity (FVC), and the body mass index (BMI) were positively associated with an increase in type I fibers in the vastus lateralis muscle in patients with moderate to severe COPD (39).

The redistribution of type I and type II fibers mentioned above might contribute to increased lower extremity muscle weakness and declined endurance. This physiological change due to reduced oxygen availability indicates a change of oxidative phosphorylation to a less efficient glycolytic capacity. More significantly, the shift to the higher number of glycolytic fibers in the quadricep muscles of severe COPD patients is linked to the metabolic derangement in muscle oxidative capacity with notably low cytochrome C oxidase and succinate dehydrogenase levels (40). In a subsequent study, the same authors reported that this low oxidative capacity could be due to a reduction in mitochondrial density in the skeletal muscle (41). Remels et al. (42) demonstrated the correlation between the substantially low mitochondrial transcription factor A and the marked reduction of mitochondrial biogenesis in the extremity muscles of cachectic severe COPD patients.

COPD also induces different adaptive changes in the upper limb muscles. Upper limb muscles include muscles in between the shoulder and elbow, which serve as important accessory respiratory muscles for ventilation. A study examining deltoid muscles in COPD patients demonstrated no clear pattern of atrophy like in lower limb muscles. Instead, three differentiated modes were observed during histomorphometry studies: normal-sized, atrophic, or hypertrophic, sometimes even within the same fascicles (43). Due to the deltoid being a respiratory accessory muscle, this hypertrophy could imply that it is being recruited to help with ventilatory movements. The idea of linking upper muscles to pulmonary function was also shown in an examination of 88 stable COPD patients, demonstrating that elbow flexor endurance has an important impact on pulmonary function and inspiratory muscle strength (44). Conversely, a different study on 89 patients with COPD found a correlation of upper limb muscle strength with exercise but none with pulmonary function (45). These differences in measurement and function could be attributed to the studies using different test methods to explain the relationship between pulmonary function and muscle strength. In another study investigating exercise functioning, grip strength, and metabonomics of the deltoid muscles in COPD patients, researchers found that handgrip strength changed unnoticeably despite a markedly reduced exercise capacity (46). Despite this, upper limb strength has also been found to impact a patient’s perceived quality of life significantly, and improving these muscles also influences exercise tolerance (47).

Physiological Changes on COPD in Muscles

Studies found that deltoid muscle creatine kinase and phosphofructokinase (PFK) activities did not differentiate between COPD and control subjects. However, the remarkedly increased citrate synthase and lactate dehydrogenase activities in patients with COPD suggested a metabolic adaptation in both mitochondrial glycolytic and oxidative capacities (46). The enzyme levels in patients with COPD were measured before and after a resistance training program to assess the physiologic muscle endurance response (48). The enzymatic activities of citrate synthase in the tricarboxylic acid (TCA) cycle and hydroxyacyl-Coenzyme A (CoA) dehydrogenase in beta-oxidation of fatty acids were significantly reduced with increased rates of lactic acid production.

Oxidative metabolism is known to be more energy efficient than glycolytic metabolism because it produces more ATP per mole of glucose. The shift toward glycolytic metabolism negatively influences the skeletal muscle bioenergetic balance of patients with COPD (49). Several studies showed early increases in blood lactate concentration in patients with COPD during submaximal-graded exercise (50). The reduction in the concentration of oxidative enzymes in lower extremity muscles has been suggested to be the reason for this early lactic acidosis (51). Intracellular glutamate is vital in preserving high-energy phosphates and is an essential precursor for synthesis of the antioxidant glutathione and glutamine in muscles. It has also been revealed that glutathione levels are significantly decreased in patients with COPD (52,53) and that the reduction in muscle glutamate is associated with premature lactic acidosis in patients with COPD during exercise (54). Muscle pathologies are a complex process that result from alterations in the intrinsic muscle bioenergetic metabolism and cell cycle regulation. COPD-associated muscle weakness and atrophy are poorly managed health problems. Repairing muscle metabolic derangement by pharmaceutical or nutritional intervention may improve control of COPD symptoms and overall disease outcomes.

Physiological Role of L-Carnitine in Health and Diseases

L-carnitine is known for its role in transporting fatty acids across the mitochondrial membrane and in the bioenergetic metabolism of fatty acids (55). About 75% of L-carnitine is consumed from food; the rest is synthesized in the liver and kidneys. Approximately 95% of L-carnitine is found in the skeletal muscle; the remaining is stored in the brain, heart, and sperm (56). The biosynthetic process of L-carnitine from lysine and methionine involves five enzymatic concerted actions as well as the involvement of iron II (Fe²⁺), L-ascorbic acid (vitamin C), pyridoxine (vitamin B6), and niacin (from nicotinamide adenine dinucleotide, NAD) (57). Carnitine binds to fatty acids and transports them across the mitochondrial membrane. In mitochondria, L-carnitine is needed for the beta-oxidation of fatty acids to produce ATP. Toxic waste from this process and drug or chemical insults are removed from the mitochondria with the aid of carnitine (58).

The human body can synthesize L-carnitine at a normal rate from 0.16 to 0.48 mg/kg of body weight/day. In healthy people, including vegans, the body is able to maintain an efficient amount of L-carnitine due to its renal reabsorption of approximately 95% (59). Thus, carnitine is both consumed through diet and produced by endogenous biosynthesis to prevent deficiency. The carnitine-rich food sources include meat, poultry, fish, and dairy. In contrast, vegetables contain relatively small amounts. Once the food is digested in the stomach, carnitine in the intestinal lumen is rapidly absorbed through the mucosal membrane via both active and passive transport (60). The liver then releases L-carnitine to the systemic circulation from the portal circulation.

L-Carnitine Deficiency

Primary systemic and myopathic carnitine deficiency are rare hereditary disorders, with myopathic deficiency being less severe. Primary systemic carnitine deficiency results from a genetic disorder detected in infancy or early childhood (57). A low concentration of L-carnitine in the blood can lead to life-threatening brain, heart, or liver damage if untreated. An underlying cause, known as carnitine carrier deficiency, is a mutation of the transport protein, which prevents L-carnitine from being carried into cells. Hence the major loss of L-carnitine through urination is due to inadequate intestinal absorption and poor renal reabsorption (61). Primary myopathic carnitine deficiency is also a genetic disorder in which carnitine deficiency is limited to the skeletal and cardiac muscle while the serum levels remain normal (62). Myalgia and progressive hypotonia are the common manifestations observed in these cases and can start in early childhood or adulthood. Secondary carnitine deficiencies can be hereditary or acquired, presenting low levels of free L-carnitine (57,61). In such cases, total L-carnitine levels may be normal, but free L-carnitine levels are reduced.

Secondary carnitine deficiency can result from inherited disorders such as propionic aciduria and medium-chain acyl-CoA dehydrogenase deficiency (62). Acquired secondary carnitine deficiency can be caused by hemodialysis, Fanconi syndrome, and the metabolic processes of certain medications or toxins, which lead to the loss of substantial L-carnitine (63). Other risk factors of secondary carnitine deficiency include malabsorption syndromes and inadequate L-carnitine intake diets (64). Premature infants are at high risk of developing secondary carnitine deficiency when no L-carnitine is added to soy-based formulas (65). Even though most dietary L-carnitine is obtained via animal-source foods, strict vegetarians can synthesize an adequate amount of L-carnitine endogenously.

Coenzyme A (CoA) facilitates the transfer of short- and medium-chain fatty acids to L-carnitine. This results in the formation of short- and medium-chain acyl-carnitines, which are transported outside the mitochondria and into the mitochondria matrix for further use (66). This process not only frees CoA for energy production and removes extra acyl and acetyl groups from the mitochondrial matrix, but also leads to L-carnitine depletion during the long-term administration of pharmaceutical drugs used for treating COPD and comorbidities (67).

L-Carnitine’s Role in Muscle Metabolism and Function

In the skeletal muscle, carnitine is vital for the subsequent beta-oxidation because it transports long-chain fatty acids into the matrix of the mitochondria. Thus, carnitine is essential in regulating muscle fuel metabolism (68) (Figure 1). As mentioned above, carnitine has also been reported as amino acid sparing supplement for new protein synthesis during exercise (69). This suggests carnitine usage in endurance exercise to promote muscular hypertrophy. A canine study has demonstrated that using carnitine supplement in animals helps minimize protein degradation due to intensive exercise (70). Both primary and secondary carnitine deficiency can result from compromised synthesis, metabolism, or transport of L-carnitine, which eventually causes the elevation of intramyocellular lipid levels in muscle tissues (71). Hypotonia and increased physical fatigue are the common signs of carnitine deficiency. The skeletal muscles store relatively 95% of total body carnitine for the physiological bioenergetics of the muscle tissues (72). Hence, insufficient carnitine levels can significantly result in skeletal muscle dysfunction, as found in primary and secondary carnitine deficiencies.

Figure 1. A schematic diagram of the metabolic roles of carnitine in skeletal muscle metabolism. Carnitine plays an essential role in the transportation of long-chain fatty acids (acyl groups) into the mitochondrial matrix for β-oxidation and the TCA cycle. The process involves active transport of carnitine into the cytosol, followed by its participation in acyl group translocation. Additionally, carnitine helps regulate the Coenzyme A (CoA)/acylCoA ratio within the mitochondria. This modulation reduces the buildup of harmful acyl-CoA compounds, ensuring efficient energy production. FATP: Fatty acid transport protein; CoA: coenzyme A; CPT: carnitine palmitoyl transferase; CACT: carnitine-acylcarnitine translocase; CAT: carnitine acetyltransferases; TCA: tricarboxylic acid cycle.

A number of studies have shown the positive influences of carnitine supplementation in exercise performance, facilitating and accelerating recovery from exercise-related muscle strain (73,74). Carnitine supplement was also found to be effective in lessening muscle damage resulting from intense or lengthening of the sarcopenic muscle contractions (75). Several animal studies and clinical trials have provided evidence of the beneficial effects of carnitine treatment in the management of various pathological disorders associated with skeletal muscle atrophy (76). In the skeletal muscle, normal force production requires low levels of reactive oxygen species (ROS) and nitrogen species. Elevated ROS levels in myofibers indicate oxidative stress, which activates pathophysiologic signaling, resulting in apoptosis and proteolysis (77). The benefits of carnitine as an antioxidant have been observed in load-induced muscle injury (78,79).

L-carnitine has important effects on both the skeletal and cardiac muscles. Since 1990, many human studies showed the effectiveness of L-carnitine in attenuating damage from muscle fatigue and hypoxia (80). It can be explained via the body’s ability to store glucose as glycogen in the muscles, which contributes to the energy-boosting effects of L-carnitine (81). In the case of children with neurofibromatosis type 1 (NF1), hypotonia and fatigue can considerably affect their quality of life. Human muscle biopsies and mouse models of NF1 deficiency in the muscle showed intramyocellular lipid accumulation, and preclinical evidence suggested that L-carnitine supplementation can ameliorate this pathology. In a recently published study, the authors investigated a daily dose of 1,000 mg of L-carnitine for children with NF1 (82). The clinical data reported the safety and effectiveness of using L-carnitine for increasing muscle strength and reducing fatigue in children with NF1 in a 12-week Phase 2 clinical trial.

Previously, several clinical studies also reported the benefits of L-carnitine supplementation for the neuromuscular function of patients with a variety of skeletal muscle disorders, including spinal muscular atrophy (83), Parkinson’s disease (84), Rett syndrome (85), and autism spectrum disorder (86). In human studies, L-carnitine also showed a protective effect on myocyte damage, eventually reducing inflammatory cytokine production in patients and athletes (55). Finally, an in vitro study of carnitine’s role in skeletal muscle remodeling, myotube formation, and differentiation showed that L-carnitine in physiological concentration accelerated C2C12 myotube formation and induced morphological changes to prevent muscle atrophy (87). Moreover, carnitine positively regulated oxidative stress defense. The collected data strongly indicate the potential therapeutic use of carnitine to manage muscle morphological and functional impairment resulting from oxidative stress, atrophy, and aging.

Possible Clinical Application of L-carnitine

Carnitine can be essential or “conditionally essential” for multiple groups of people diagnosed with genetic, infectious, and injury-related diseases. Numerous published data support treatments of myocardial dysfunctions and other cardiovascular diseases with L-carnitine supplementation (88-93). Patients with primary carnitine deficiency could fully reverse clinical manifestations with one month of oral carnitine therapy (94,95). Secondary carnitine deficiency cases, such as patients with kidney disease and very long-chain acyl-CoA dehydrogenase deficiency, also benefited from carnitine supplementation (96,97). L-carnitine therapy may also be used for Alzheimer’s diseases (98-100) and other neurodegenerative disorders (101), epilepsy (102,103), depression (104,105), physical and mental fatigue (106,107), pain and neuropathies (108,109), macular degeneration (110), diabetes and diabetic neuropathy (111-114), chemotherapy induced neuropathy (115,116), sexual dysfunction (117-119), hypothyroidism (120), support for kidney failure and patients on dialysis (121-123), asthma (124), and COVID-19 (125,126). Anecdotal uses of L-carnitine include a decrease of cognitive function with aging, peripheral neuropathy (secondary to trauma), HIV infection, immune function cerebral hypoxia, ischemic reperfusion injuries (127), Peyronie’s disease, cerebral ataxia, attention deficit hyperactivity disorder (ADHD), Down’s syndrome (128), facial paralysis, male infertility (129), pulmonary tuberculosis (130), diminished cognitive function due to alcoholism, chronic fatigue syndrome (131), Parkinson’s (132), amenorrhea and others.

L-Carnitine in the Management of Patients With COPD

L-carnitine deficiency has been observed in patients with COPD. Compared to healthy control subjects, the total carnitine levels are noticeably lower in patients with COPD. Moreover, patients with severe COPD are shown to have a tremendous decrease in carnitine levels compared to patients with mild COPD. Frequent exacerbations may worsen the long-term prognosis of patients with COPD. Conventional management of COPD exacerbations mainly focuses on symptom-relieving and restoration of functional capacity with oxygen replacement, β₂-agonists, anticholinergics, antibiotics, and systemic corticosteroids. In a prospective clinical study, Elammak and colleagues reported using L-carnitine for supportive effects on fatty acid and glucose metabolism and the possible prevention of wasting syndrome (133).

Bao Khi Khang is a nutritional supplement with a unique combination of L-carnitine fumarate and natural herbal ingredients used in traditional Vietnamese and Chinese Medicine to enhance neuromuscular function. In a randomized control clinical study, the therapeutic effect of Bao Khi Khang as conventional therapy alone and adjunctive therapy was investigated for acute exacerbations of COPD (4). COPD exacerbations were significantly reduced in patients treated with the combination of Bao Khi Khang tablets and standard therapeutic protocol. The favorable progress of COPD assessed before and after treatment between the experimental and control groups was statistically different. Symptoms such as cough, copious sputum secretion, and bacterial infection were relieved by 90% (very good 50.0%, good 40.0%) in the experimental group and 50% (very good 20%, good 30.0%) in the control group (4). No adverse effects were reported in the experimental group. The data from this study showed that L-carnitine could be used effectively and safely in adjuvant therapy in acute exacerbations of COPD. In another clinical trial, a daily dose of 2000 mg of L-carnitine showed enhancement in exercise tolerance and respiratory muscle strength in patients with COPD. In addition, a reduction in serum lactate levels was reported in patients with L-carnitine therapy (134).

Cachexia, a morbidity developed in 20 to 40% of COPD patients (135,136), is a complicated metabolic syndrome resulting from an underlying illness denoted by muscular atrophy with or without fat mass loss and often accompanied by signs of systemic inflammation and anorexia. Cachexia in patients with COPD can lead to poor quality of life, reduced function capacity, and a higher risk of morbidity and mortality (29,137). Various studies have shown L-carnitine benefits patients with COPD and cancer-related cachexia (Table I). Low blood concentration of carnitine in cachexic patients with COPD could have resulted from inadequate dietary intake, impaired endogenous synthesis, or side effects of prolonged pharmacological therapy. In this context, supplementation of L-carnitine may produce the same therapeutic effects as shown in cachexic patients with cancer (138-140).

Table I. L-Carnitine in chronic obstructive pulmonary disease (COPD) patients management.

(I): Intervention; (P): Placebo; (C): Control.

L-Carnitine Doses, Side Effects, and Interactions

Generally, L-carnitine is a well-tolerated and non-toxic substance. A typical daily diet contains 5 to 100 mg of carnitine, depending on whether the diet is primarily plant-based or meat-based (17). Depending on various health conditions, recommended L-carnitine doses range from 300-2,000 mg/day. Possible adverse effects are rare and mild gastrointestinal irritations, including nausea, vomiting, abdominal cramps, diarrhea, increased appetite, and rashes are observed (82). In clinical investigations, supplements providing up to 3,000 mg/day have shown no short-term and long-term side effects or negative interactions with conventional drugs for both children and adults (66).

Discussion and Perspectives

Multiple chronic diseases are shown to be related to decreased cellular energy production and nutrient-resistant progressive myopathy with accelerated proteolysis, reduced physical function, and survival rate (66,141). Skeletal muscle dysfunction is a common comorbidity in patients with COPD resulting in worse clinical outcomes, higher hospitalization rates and costs, poor quality of life, and higher mortality. Muscle dysfunction in COPD is a systemic pathologic condition that requires a long-term and gentle holistic approach to management. Systemic factors may include inflammation, nutritional depletion, corticosteroid use, chronic inactivity, age, hypoxemia, smoking, oxidative stress, enhanced proteolysis, and poor vascularization (10). A significant amount of scientific data shows that metabolic alterations in the muscle tissue may cause unfavorable conditions that lead to pathological skeletal muscle dysfunction, weakness, and atrophy (12,13). New research activities continue to shed light in the molecular mechanisms underlying muscle dysfunction and its consequences in patients with COPD. However, the management of muscle dysfunction in COPD is mainly symptomatic and reactive with physical therapy and exercise, but no specific pharmacologic therapy is currently available. Multiple factors can cause both primary and secondary L-carnitine deficiency in patients with COPD. Most total body carnitine is stored in the skeletal muscle and is readily utilized for the muscle tissues’ bioenergetic processes. Previous research examined the positive influences of carnitine supplements on physical performance, suggesting the role of carnitine as a metabolic regulator of skeletal muscle fuel utilization, bioenergetic metabolism, and physiological function (17,142). Several clinical investigations indicate a remarkable benefit of L-carnitine and derivatives as an ergogenic aid and adjuvant therapy for COPD exacerbation, muscle metabolic derangement, and respiratory manifestations of COPD as a whole (4,133,134).

Considering the lack of proven effective and safe therapies for muscle dysfunction and related health disorders, there is a need for research and study into nutritional supplements that might support muscle energy metabolism and muscle damage control. The available clinical data and evidence of a beneficial physiological role in muscle biochemistry and cellular bioenergetics highly support the rationale of implementing L-carnitine and derivatives for managing patients with COPD. Another rationale for its use in the wasting syndrome in patients with COPD is the induced muscle weakness, hypotonia, neutral lipid storage disease (predominantly in type I fiber), and myolysis (type II fiber atrophy) associated with carnitine deficiency (142).

Given that L-carnitine is readily available as an inexpensive and safe nutritional supplement, it can be implemented in the early stages of muscle dysfunction and wasting, potentially preventing disease progression, and improving the prognosis of patients with COPD. Mitochondrial β-oxidation is a major source of cellular energy. The increased oxidative stress has been associated with the inefficiency of cellular bioenergetic metabolism due to intrinsic and extrinsic factors, contributing to the development of inflammatory disorders, abnormal tissue remodeling, and degenerative and proliferative diseases (66,141). Usage of L-carnitine for optimal mitochondrial function can have multiple therapeutic benefits for patients with COPD, such as reduction oxidative damage, anti-inflammation, optimization of tissue remodeling, preservation of body mass, prevention and improvement of cachexia, reduction of fatigue, and improvement of performance.

Finally, L-carnitine administrations have shown viable clinical effectiveness for many acute and chronic pathologic conditions such as cardiovascular diseases, congestive heart failure, diabetes, diabetes-related illnesses, infections, intoxications, osteoporosis, pharmaceutical drug side effects, neuromuscular disorders, and more. The application of L-carnitine in this context is even more relevant since many patients also suffer from one or more of the above-mentioned diseases as comorbidities.

In our view, the management of COPD as a chronic disease should be shifted from symptomatic reactive pharmaceutical intervention to a more constructive and non-toxic approach using a single or combination of natural and nutritional agents with potential muscle metabolic enhancing and immunomodulating activities to achieve a better overall outcome for the patients in terms of morbidity, mortality, and medical cost.

Conclusion

Conventional strategies for chronic diseases such as COPD heavily focus on developing and applying pharmaceutical drugs. Hundreds to millions of patients with COPD worldwide have to live and experience damaging consequences of chronic inflammatory symptoms, breathing difficulties, poor functional performance, and poor quality of life. Additionally, the frequent exacerbations, high cost of maintaining therapy, hospital care, widespread comorbidity, and adverse drug effects make COPD the third leading cause of death and one of the biggest global health problems. As inexpensive, safe, and proven-effective for various acute and chronic human diseases, L-carnitine and its derivatives should be explored and implemented as nutraceutical or adjuvant therapeutics for patients with COPD to improve disease outcomes and quality of life. Since L-carnitine is a non-patentable nutritional agent, pharmaceutical organizations lack interest in promoting and funding research and application of L-carnitine for any health problems. More doctor-initiated and publicly funded clinical trials are needed to optimize dosing and regimen for L-carnitine supplementation therapy in patients with COPD.

Conflicts of Interest

The Authors have no conflicts of interest to disclose in relation to this study.

Authors’ Contributions

Ba X Hoang: Conceptualization, Visualization, Writing – original draft, Writing – review & editing, Bo Han: Conceptualization, Visualization, Writing – original draft, Writing – review & editing, William Fang: Prepared the tables, figure, Writing – review & editing, Anh K. Nguyen: Writing – review & editing, David G. Shaw: Writing – review & editing, Cuong Hoang: Writing – review & editing, Hau D. Tran: Writing – review & editing. All Authors read the manuscript prior to submission.