Is dietary L-carnitine a strategy to combat COPD-induced muscle wasting?

PVRI Member Authors: Robert Ringseis


 Loss of skeletal muscle mass, also known as muscle wasting, is a common symptom of several chronic diseases, such as cancer, infectious diseases, and chronic obstructive pulmonary disease (COPD). Due to the strong negative impact of muscle loss on patients’ prognosis and quality of life, the development of efficacious treatment approaches to combat muscle wasting are of great importance. Interestingly, several clinical studies demonstrated that supplementation of L-carnitine (LC) has beneficial effect in patients with chronic diseases associated with muscle wasting. LC is a water soluble quaternary amine (3-hydroxy-4-N,N,N-trimethylaminobutyric acid) which is essential for normal function of all tissues with the most documented function being the translocation of long-chain fatty acids from the cytosol into the mitochondrial matrix for subsequent β-oxidation. LC in the body originates from both dietary sources (meat and dairy products) and biosynthesis in liver and kidney. LC biosynthesis probably contributes most to the whole body LC pool. This can be deduced from the observation that plasma LC levels in vegetarians, which take up only negligible amounts of LC through the diet, are only 15-30 % lower than those in nonvegetarians, being yet within the normal physiological range of 25-50 µM. The plasma LC levels in vegetarians can be maintained within the normal range because they have a more efficient renal re-absorption of LC and a greater rate of LC biosynthesis. In vegetarians, LC deficiency may develop only if certain micronutrients, such as ascorbic acid, pyridoxine and iron, required as co-factors for LC biosynthesis are not provided from the diet in sufficient amounts. Noteworthy, LC was found to improve quality of life measures, nutritional status and body condition, to reduce fatigue-related symptoms and to decrease markers of oxidative stress and inflammation in patients with chronic diseases such as cancer, chronic kidney disease (CKD), HIV or hepatic encephalopathy [1-5]. In addition, a recent experimental study showed that LC reduces proteolysis in skeletal muscle, increases muscle weights and improves parameters of physical performance in tumourbearing rats [6]. Whether LC is also effective as an anti-wasting agent in COPD patients is currently unknown. The following discussion summarizes results from animal and clinical studies showing beneficial effects of supplementation with LC or LC derivatives (acetyl-LC, propionyl-LC) on critical mechanisms involved in skeletal muscle loss under pathologic conditions, such as increased proteolysis, impaired protein synthesis, myonuclear apoptosis, inflammation, oxidative stress, and mitochondrial dysfunction. Finally, this article aims to provoke the community to think about a possible beneficial effect of LC supplementation in COPD patients.

Evidence for Inhibition of Protein Degradation

 Recently, LC was found to cause a downregulation of critical components of the ubiquitin proteasome system (UPS), the most important cellular system of protein breakdown, in gastrocnemius muscle of tumour-bearing rats [6]. This effect was accompanied by an inhibition of tumour-induced muscle wasting and an improvement of physical performance. Also in healthy animals, it was found that LC decreases gene expression of critical UPS components in skeletal muscle [7]. This effect of LC has been attributed to a stimulatory effect on the insulin like growth factor (IGF) axis [8,9]. In patients with endstage CKD it was observed that LC causes lower rates of leucine oxidation and wholebody leucine appearance from proteolysis during euglycemic hyperinsulinemic clamp conditions [10]. This indicates that LC has protein-sparing effects. In another clinical trial it was found that LC attenuates post-stress metabolism in surgical patients [11].

Evidence for Stimulation of Protein Synthesis

 In rats and piglets which received total parenteral nutrition (TPN) containing LC, a greater nitrogen balance was observed [12,13], effects that were ascribed to increase energy production from fatty acid oxidation thereby causing a sparing of protein mass. In rats under unloading conditions it was found that acetyl-LC has a hypertrophic effect on type I fibers and favors a slow-oxidative phenotype of soleus muscle [14]. Likewise, Vescovo et al. [15] observed in a rat model of chronic heart failure (CHF) that LC causes an increase in the cross-sectional area of tibilias anterior muscle. In this context, Moriggi et al. [16] observed in rats under unloading conditions that acetyl-LC counteracts the unloading-induced change in muscle phenotype (shift from slow-oxidative to fast-glycolytic). This suggests that LC is able to prevent the metabolic shift from oxidative to glycolytic skeletal muscle in unloaded animals. In humans, direct parameters of protein synthesis have not been assessed in response to dietary carnitine. However, two clinical studies reported that supplementation of either LC or acetylLC increases serum concentrations of IGF1 in β-thalassaemic patients and asymptomatic HIV patients, respectively [17,18]. Bellinghieri et al. [19] reported that LC reduces muscle cramps in a group of uremic patients on intermittent hemodialysis (HD). Noteworthy, two previous studies reported trophic effects of LC on skeletal muscle in CKD patients undergoing HD [20,21].

Evidence for Inhibition of Apotosis

In a rat model of monocrotaline-induced CHF, LC reduced markers of apoptosis in tibialis anterior muscle [15]. An inhibitory effect of LC on staurosporine-triggered apoptosis was also observed in cultured mouse C2C12 myotubes indicating that the anti-apoptotic effect of LC on skeletal muscle is a direct effect on myofibers. In addition, LC was demonstrated to inhibit apoptosis in gastrocnemius muscle in a genetic mouse model of human amyotrophic lateral sclerosis [22] and in tumour-bearing rats [6]. No clinical studies are available from the literature evaluating an effect of LC on myocyte apoptosis or signalling pathways regulating apoptosis in skeletal muscle. However, it has long been known that apoptosis of lymphocytes in HIV infection has great significance and lymphocyte apoptosis correlates with disease progression. Thus, severalclinical studies have evaluated an effect of LC on lymphocyte apoptosis in HIV patients [17,23,24]. Indeed, in three studies LC was followed by a significant reduction of lymphocyte apoptosis in HIV-infected patients. Indirect proof for an anti-apoptotic effect of LC was provided from two other studies in HIV patients in showing that LC increases proliferation of peripheral blood mononuclear cells and/or elevates the frequency of lymphocytes entering the S and G2-M phases of the cell cycle following mitogen stimulation [25,26].

Evidence for Inhibition of Inflammation

 Animal studies consistently showed that LC exerts anti-inflammatory effects under pathologic conditions. In rats LC prevented the increase in serum tumor necrosis factor (TNF)-α levels induced by methotrexate [27]. In addition, LC produced a significant decrease in serum TNFα levels in a rat model of CHF which was associated with an inhibition of CHF-induced myopathy and skeletal muscle apoptosis [15]. Moreover, in a rat model of hypertension chronic administration of LC attenuated the inflammatory process associated with arterial hypertension [28]. Furthermore, LC was found to decrease plasma levels of cytokines in methylcholanthrene-induced sarcoma-bearing rats indicating that carnitine may ameliorate cancer cachexia through attenuating tumourassociated inflammation [29]. Also in a rat model of acute renal failure, LC was found to exert an anti-inflammatory action [30]. Using a mouse model of cancer cachexia, Liu et al. [31] observed that LC supplementation decreases plasma levels of TNFα and interleukin (IL)-6, again suggesting that carnitine inhibits cancer cachexia by reducing serum levels of cytokines which are considered as key factors for protein catabolism [32]. LC appears to be beneficial in humans as well. In a study with AIDS patients undergoing antiviral therapy LC caused a significant reduction of circulating levels of TNFα [25]. In addition, LC caused a significant reduction in plasma levels of C-reactive protein (CRP) and TNFα in patients with nonalcoholic steatohepatitis [33]. A strong anti-inflammatory effect of LC was also observed in (non-cancer) patients undergoing surgery indicating that LC protects surgical patients against surgery-induced systemic inflammation [34]. Moreover, LC causes anti-inflammatory effects in HD patients [35,36]. Interestingly, in some of these studies LC supplementation was accompanied by increases in body mass index and serum albumin levels indicating that LC supplementation improves nutritional status and causes an anti-wasting effect.

Evidence for Prevention of Oxidative Stress

 Several lines of evidence from animal experiments exist that LC is effective in preventing oxidative stress under various pathological conditions. Dutta et al. [37] reported significant reductions in markers of oxidative stress and an increase in creatine kinase activity (an indirect marker of muscle damage) in gastrocnemius muscle and improvements of several indicators of muscle performance in LC-supplemented rats subjected to intermittent hypoxia. In another study, LC was effective in alleviating fructose-induced oxidative stress in rats [38]. In addition, LC suppressed oxidative modification of proteins in the hind limb muscle in a transgenic mouse model of amyotrophic lateral sclerosis [22]. Furthermore, Breitkreutz et al. [39] showed higher intramuscular levels of glutathione in tumor-bearing mice treated with LC suggesting a LC-mediatedimprovement of the muscular antioxidant status in malignant diseases. Apart from this, a great number of animal studies consistently showed an anti-oxidative potential of LC in non-muscle tissues of different animal models of oxidative stress [40-44]. In humans, LC was shown to be effective in attenuating oxidative stress responses in two studies with either HIV patients [45] or CKD patients undergoing HD [46]. Moreover, in a double-blinded, placebo-controlled study with type 2 diabetic patients LC caused a significant reduction in the levels of oxidative stress markers [47]. Supplementation of LC immediately before surgical intervention was also found to be helpful in preventing major abdominal surgery-induced oxidative stress as assessed by platelet reactive oxygen species (ROS) production [48].

Evidence for Amelioration of Mitochondrial Function

 An effect of LC on mitochondrial function was investigated in an experimental model of traumatic spinal cord injury (SCI), which is characterized by extensive tissue damage and mitochondrial dysfunction. Patel et al. [49] found that administration of acetyl-LC after thoracic SCI significantly maintained mitochondrial function at the injury site and daily acetyl-LC treatment increased spinal cord tissue sparing. In another study with a more severe contusion SCI model, acetyl-LC treatment resulted in significant improvements in acute mitochondrial bioenergetics and long-term hind limb function indicating that acetyl-LC promotes neuroprotection by preventing mitochondrial dysfunction [50]. Also in a mouse model of high fat diet-induced obesity propionyl-LC improved mitochondrial function [51]. In a rat model of severe cardiac hypertrophy, propionyl-LC restored the degree of reduction of mitochondrial pyridine nucleotides and improved the kinetics of mitochondrial ATP production in volumeoverloaded hearts [52]. Likewise, propionylLC was effective in improving mitochondrial respiration and ATP production in a rat model of cardiotoxicity in which mitochondrial function is also impaired [53]. Only few studies have been conducted to explore an effect of LC on mitochondrial function in subjects with wasting-associated chronic diseases. In one study from Milazzo et al. [54] it was reported that acetyl-LC increased both 13CO2-exhalation and cumulative 13CO2 excretion as well as mitochondrial DNA content of CD4+ T-cells in HIV patients with antiretroviral therapy-related lipoatrophy indicating a protective role of acetylLC on mitochondrial function. A protective effect of acetyl-LC on mitochondria was also proposed by Cossarizza et al. [24] based on their finding that significantly less cells with depolarized mitochondria were found following incubation of peripheral blood lymphocytes from HIV patients with acetyl-LC.

Summary and the Question for Interactive Discussion

 Comprehensive analysis of results from both animal and clinical studies shows that LC supplementation beneficially influences several critical mechanisms involved in skeletal muscle loss under pathologic conditions, such as increasing protein synthesis, reducing protein degradation, inhibiting apoptosis, abrogating inflammation, preventing oxidative stress and ameliorating mitochondrial function. Based on the fact that similar mechanisms are known to be involved in COPD, we would like to postulate the following question: Could supplementation with Journal Club Interactive discussion: Is dietary L-carnitine a strategy to combat COPD-induced muscle wasting? 39 LC serve as an effective anti-wasting approach for patients with COPD?

 From our point of view, COPD patients might benefit from LC supplementation because LC status is frequently impaired, e.g. plasma LC levels are reduced, in chronically ill patients [55-57] as a consequence of a reduced food intake, which is accompanied by a decreased dietary uptake of LC and specific micronutrients required as cofactors for LC synthesis. In addition, it has been reported that pharmacotherapy in chronically ill patients often causes an impaired LC status as a side effect due to a reduction of LC absorption from the intestine and/or a stimulation of urinary LC excretion [58,59]. A reduction of intestinal LC absorption might be relevant in COPD patients undergoing treatment with the anticholineric drug ipratropium due to competition for the same transport mechanism in the intestine, namely the active transport by the sodium-dependent novel organic cation transporters OCTN1 and OCNT2. Indeed, ipratropium was reported to be a strong inhibitor of OCTN2-mediated LC uptake [60]. Irrespective of the efficacy of dietary LC supplementation as an anti-wasting approach in COPD patients, it is worth to mention that none of the clinical studies dealing with LC supplementation reported any adverse effects even at very high dosages, at least in the short-term. However, with regard to possible adverse effects of long-term LC supplementation, one recent study has to be mentioned showing that chronic dietary LC supplementation in mice alters cecal microbial composition, markedly enhances synthesis of trimethylamine (TMA) and the proatherogenic species trimethylamine-N-oxide (TMAO), and increases atherosclerosis [61]. Moreover, these authors reported that omnivorous subjects produce significantly more TMAO than vegans/ vegetarians following ingestion of LC through a microbiota-dependent mechanism. In light of these recent findings safety aspects of chronic LC supplementation have to be critically evaluated. Scientists and other persons who are interested in this field are invited to express their views, pro or contra, about this topic in the next issue of PVRI Chronicle.



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Oxidative stress and Oxidants/Antioxidants and Free Radicals

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