Nutraceuticals for Duchenne Muscular Dystrophy: Comparison
View Latest Version
Please note this is a comparison between Version 2 by Jason Zhu and Version 1 by Boel De Paepe.

Duchenne muscular dystrophy (DMD), the severest form of muscular dystrophy, is characterized by progressive muscle weakness with fatal outcomes most often before the fourth decade of life. Despite the recent addition of molecular treatments, DMD remains a disease without a cure, and the need persists for the development of supportive therapies aiming to help improve patients’ quality of life.

  • N-acetylcysteine
  • amino acid supplements
  • L-arginine
  • taurine

1. Introduction

The severest form of muscular dystrophy (MD), termed Duchenne MD (DMD), is a progressive muscle-wasting disease. Its first symptoms usually occur at 2 to 3 years of age, and most patients become wheelchair-dependent when they reach their teens. In addition to accumulating skeletal muscle weakness, respiratory insufficiency and cardiomyopathy develop [1]. The disease is caused by mutations in the protein-coding DMD gene, which leads to the absence of functional dystrophin protein and the disconnection of the intracellular muscle fiber cytoskeleton from the extracellular matrix and the basal lamina. Via complex cascading pathways, sarcolemmal damage accumulates, resulting in muscle fiber necrosis and replacement with connective and fatty tissue [2]. The chronic inflammation that damages muscle tissues in DMD patients is counteracted by immunosuppressive therapy, which delays loss of ambulation and prolongs life expectancy, but comes with important side effects [3]. Despite intensive efforts in therapeutic innovation, DMD remains incurable to date. There are several promising novel therapeutic approaches for DMD that are entering the clinic; however, their limitations suggest that future disease management may still require the combination of molecular interventions with pharmacological agents [4]. The search for supportive therapies remains, therefore, valuable and worthwhile. Therapeutic development is facilitated by the availability of animal models such as the mdx mouse, the standard model for DMD. Despite genetic similarities to the human condition, the disease phenotype of mdx is much milder, exhibiting less severe skeletal muscle damage, with the notable exception of the diaphragm muscle [5].
A well-balanced diet is paramount to patient wellbeing, yet the progressive nature of DMD disease poses particular challenges. Many patients struggle with constipation and weight gain due to progressive muscle weakness and limited mobility. The prolonged therapeutic use of glucocorticoids further adds to the risk of developing obesity and related endocrine complications. Caloric intake needs to be balanced with physical activity to manage weight throughout the different disease stages, requiring personalized dietary advice and strategies adjusted throughout the patient’s life [6]. Recommendations to assess nutritional status and its associations with therapies, and guidelines for nutrient management and supplementation have been published [7]. Nutritional advice for DMD aims to preserve lean muscle mass and prevent excessive fat build-up and weight gain, assuring sufficient intake of protein. Other issues of concern are the prevention of osteoporosis and balanced calcium intake, and maintaining normal cholesterol and lipid levels through saturated fat moderation. Moderation of refined carbohydrate intake to avoid insulin resistance is recommended, and sufficient intake of dietary fibers is advised to prevent constipation. No international guidelines have been proposed for dietary supplements in DMD, except for the need for vitamin D and calcium supplementation when patients display a deficiency.

2. Amino Acid Supplementation as a Therapeutic Strategy for DMD

The human body needs amino acids to build up tissues, and for the regulation of a multitude of intracellular biochemical pathways. All natural amino acids concern the left-handed (L) stereoisomers. Their basic structure consists of four groups attached to a central carbon: a hydrogen, an α-carboxyl group, an α-amine group, and a side chain. Twenty two amino acids are proteinogenic, i.e., used to build up proteins. Instructions for the correct amino acid sequence that makes up a protein lie encoded in the DNA. tRNAs deliver amino acids to the ribosome, where polypeptides are generated by matching to the codons in mRNA. A subset of amino acids needs to be ingested via food, as they cannot be synthetized by human cells; these are termed essential amino acids. The essential amino acids are histidine (His), isoleucine (Ile), leucine (Leu), lysine (Lys), methionine (Met), phenylalanine (Phe), threonine (Thr), tryptophan (Trp), and valine (Val). The remaining nonessential proteogenic amino acids are glutamine (Gln), aspartate (Asp), glutamate (Glu), arginine (Arg), proline (Pro), cysteine (Cys), selenoCys, asparagine (Asp), serine (Ser), glycine (Gly), and tyrosine (Tyr). Amino acids can become chemically modified after they have been incorporated into a protein through posttranslational modification, most importantly through phosphorylation, carboxylation, and hydroxylation, strongly influencing protein function, localization, and cell signaling. A subset of amino acids are termed conditionally essential, including the 2-aminoethanesulfonic acid termed taurine (Tau) and Cys [11][8]. Semi-essential amino acids need to be ingested to uphold sufficient levels at set times, during infancy, or in certain health conditions. Diverse naturally occurring amino acid-like structures exist, and many more can be synthetically engineered. Balanced amino acid levels are a prerequisite for the preservation of protein homeostasis, hence the correction of the amino acid level disturbances associated with DMD is an amenable therapeutic strategy. In this respect, decreased circulating Tau levels have been recorded in wheelchair-bound but not in younger ambulant DMD patients, when compared to age-matched healthy boys [12][9]. Altered amino acid contents have also been observed in a mouse model, displaying age- and muscle group-dependent differences and differences between studies. In quadriceps of 3 months and 6 months old mdx, Glu and Gln levels were higher, and Gly levels were lower than in controls. In the diaphragm, higher levels of Glu, Gln, and Ile were observed in three-month-old mdx and Ala, Glu, and Ile in six-month-old mdx. Met and Tau levels in diaphragm muscles were lower in the six-month-old mdx compared to control animals [13][10]. In quadriceps of seven-week-old mdx, the levels of Met, Gly, Glu, and Tau were reduced; however, by the age of seventeen weeks Gly and Glu levels became higher than in control mice. These authors reported Met and Tau levels were lower in mdx quadriceps of both ages [14][11]. Another study, however, found that Tau levels were low in mdx of 4 weeks old, and not at the age of 6 weeks [15][12]. From the above studies, complex dysregulation of amino acid levels in different muscle groups and at different ages became apparent. Many amino acids display synergistic antioxidant activity, i.e., they enhance the effects of primary antioxidants via chelation of pro-oxidative metal traces and via regeneration of oxidized primary antioxidants. Within the proteogenic amino acids, Trp, Met, His, Lys, Cys, Arg, and Tyr have greater antioxidative capacities. The natural non-proteinogenic amino acid β-Alanine has been proposed as an especially potent scavenger of reactive oxygen species (ROS), with positive effects on muscle performance [16][13]. The non-essential amino acid Cys is required in the synthesis of the major intracellular antioxidant glutathione [17][14]. The Cys derivative N-acetylcysteine (NAC) has antioxidant properties, both directly, exerted through ROS scavenging by its thiol group, and indirectly, as a precursor of Cys. NAC has been observed to reduce oxidative damage and inflammatory changes in muscle cells in vitro [18][15], and to improve fatigue resistance and increase Cys levels in skeletal muscle tissues [19][16]. Various amino acid-like structures possess osmoprotective activities and are termed osmolytes. Tau is the most studied osmolyte in the context of DMD. Promising results continue to accumulate for Tau treatment in mdx mouse models, showing improvement of muscle strength and reduction of tissue inflammation and oxidative stress [20][17]. The osmoprotective Gly derivative trimethylglycine (TMG), or betaine, has also been observed to improve muscle performance [21][18]. TMG is obtained from the diet or via choline oxidation, and becomes further oxidized in the liver, thus forming the osmolytes dimethylglycine and trimethylamine-N-oxide [22][19]. The mechanism by which TMG supplementation affects muscle strength is elusive, but is presumed to be related to an increase in creatine, the energy substrate for muscle contraction [23][20]. Interestingly, the ratio of TMA to creatine correlates with muscle function and is decreased in DMD patients [24][21]. The osmolyte 1,4,5,6-tetrahydro-2-methyl-4-pyrimidinecarboxylic acid or ectoine (Ect) is a cyclic amino acid derived from extremophiles with therapeutic potential. Ect is a potent cell protectant that can be accumulated or removed to counteract osmotic stress. It forms a hydration shield that protects the functionality of macromolecules inside cells, acting against protein denaturation and misfolding [25][22]. Often, the osmoprotective and antioxidant activities of amino acids are observed to join forces. Tau, for instance, also possesses potent thiol antioxidant activity in muscle tissue [26][23]. Cys and its derivative L-2-oxothiazolidine-4-carboxylate (OTC) are metabolized to Tau, and OTC treatment increases Tau content, thereby improving muscle function in mdx [27][24]. As high doses become cytotoxic, tissue Cys content is under tight regulation, with excess Cys converted to Tau [28][25]. Tau also protects against the loss of muscle mass and reduced functionality associated with aging [29][26]. The protective effects of Tau have now been shown to also include preserved calcium homeostasis, membrane stabilization, and attenuation of apoptosis. Further, as Tau is able to restrain nuclear factor κB (NFκB) activity, a central regulator of tissue inflammation [30][27], Tau supplementation has been proposed as a more general anti-inflammatory strategy for various chronic inflammatory diseases. The described complex multifaceted cell protective effects of amino acids can be of benefit to ameliorate muscle tissue stress in human diseases, and could therefore be considered a supportive therapy for DMD.

3. Pre-Clinical Studies Evaluating Amino Acids and Derivatives in Mdx

The most widely used animal model for studying DMD is the mdx mouse. Mdx are of C57BL/10ScSn background and carry a nonsense point mutation (C-to-T transition) in exon 23 of the dmd gene [31][28]. Even though mdx mice are equally as dystrophin protein-deficient as DMD patients, the disease phenotype is much milder. Unlike the human disease course, skeletal muscle from 12 weeks onwards achieves relative stability of function, owing to robust tissue regeneration. Only the diaphragm shows progressive deterioration, mimicking progressive disease in affected humans. Other animal models are available, including mdx mice of a genetic DBA2/J background (D2-mdx), displaying more severe muscle function impairment and tissue fibrotic damage [32][29]. The cardiac phenotype of mdx is also less severe compared to human disease, which often progresses toward a lethal dilated cardiomyopathy [33][30]. Cardiac compensatory processes appear to depend on preserved mitochondrial content and increased efficiency of oxidative phosphorylation, driving successful regulation of calcium homeostasis in heart cells in the early mdx disease stages [34][31]. Nonetheless, mdx mice remain a valuable model to test therapeutic interventions, not in the least because of extensive knowledge of the model. The mdx disease phenotype can be aggravated by subjecting mice to strenuous exercise. Other strategies to achieve disease characteristics more resembling severe disease in humans are the genetic elimination of utrophin and α7-integrin, generating double-knockout strains with aggravated muscle disease; however, such models are difficult to breed and maintain. Preclinical studies in mdx have identified compound-specific beneficial effects on skeletal muscle tissue properties. In addition, attenuated myocardial inflammation and fibrosis and improved cardiomyocyte calcium handling have been described after NAC treatment [58][32]. NAC has also been observed to improve lung function in mdx [51][33]. However, in addition to individual effects, combinations of amino acids may have added value as a therapeutic strategy. In this respect, the essential amino acids Val, Leu, and Ile, jointly termed branched-chain amino acids (BCAA), are often combined. Experimental evidences suggest that in various human diseases, BCAA levels are reduced [59][34]. Reduced levels of BCCA may affect the body glutamate–glutamine pool, leaving the tissue more vulnerable to oxidative stress, and in such incidences, BCAA supplementation may be beneficial. The anabolic properties of BCAA appear especially useful for ameliorating skeletal muscle atrophy via a dual mechanism: stimulation of protein synthesis on the one hand, through activation of the mTOR signaling pathway, and inhibition of protein breakdown on the other hand, through curbed Atrogin-1 and MuRF-1 expression reducing Ub-proteasome activity [60][35]. Through stimulation of protein synthesis, BCAAs have been observed to ameliorate exercise performance, enhance muscle strength, and reduce fatigability [61[36][37],62], with positive effects on stamina also observed in mdx [57][38].

4. Combining Amino Acid Supplements with DMD Standard of Care

Nutraceuticals can never be curative, and can only offer valuable support to patients’ overall wellbeing. It is therefore paramount to evaluate how they perform in combination with the standard of care for DMD, as well as with the treatment regimens of the future. With optimal management of cardiopulmonary dysfunction, patients with DMD can nowadays survive to live in their forties. Immunosuppression represents a cornerstone of therapy for achieving increased life expectancy, yet the spectrum of adverse reactions associated with long term steroid use is an incentive for the development of alternative compounds [63][39]. Meanwhile, nutritional supplements could counteract some glucocorticoid-induced side effects, which include osteoporosis, obesity, short stature, delayed puberty, and adrenal insufficiency. Evidencing their positive effects on weight and metabolism, mice fed with a diet enriched with free essential amino acids were leaner and had improved metabolic parameters [64][40]. An inverse association between higher dietary BCAA intake and odds of obesity has also been described in humans [65][41]. Nonetheless, it is heavily debated whether BCAA protect against or promote insulin resistance. Either way, a large number of studies confirm an association between increased plasma levels and insulin resistance, appointing BCAA a role as biomarkers [66][42]. The impact of BCAA supplementation on metabolism is complex, and remains partly elusive. In mice on a high-fat diet, adding BCAA to the chow improves insulin tolerance, yet this effect is completely reversed by exercise training [67][43]. In obese humans on a hypocaloric diet, BCAA supplementation was not observed to affect lean muscle mass or insulin sensitivity, and a high-protein diet was suggested to be more advantageous [68][44]. Several amino acids and amino acid metabolites are associated with bone health and could be considered as dietary supplements to prevent osteoporosis. Supplementing essential amino acids increased bone strength in rats on an isocaloric diet [69][45]. A study reported BCAA and Ala in women and Trp in men as the most important amino acids inversely associated with osteoporosis in people of advanced age [70][46], and higher Trp serum levels predicted a low risk of osteoporotic fractures [71][47]. Oxidized Trp promotes bone marrow stem cells’ differentiation into osteoblasts [72][48]. Another possible bonus of amino acids could be the enhancement of anti-inflammatory effects. One could speculate that supplementation would reduce the necessary doses of glucocorticoids and/or enhance the therapeutic efficacy. The feasibility of this strategy is supported by two studies in mdx reporting that combining deflazacort with an Arg supplement improves histological and functional characteristics [39][49], and Gly supplementation augments the benefits of prednisolone treatment to diaphragm fibrosis [45][50]. Molecular therapies with different mechanisms of action are currently entering the clinic for DMD at an accelerated pace. In a first molecular strategy, the splicing process of dystrophin is altered, bypassing an out-of-frame mutation with antisense oligonucleotides [73][51]. Preservation of the dystrophin reading frame allows for the production of partially functional dystrophin, thereby reducing the severity of the disease phenotype. Several such exon-skipping therapies have been approved by the Food and Drug Administration to date: eteplirsen [74][52], golodirsen [75][53], viltolarsen [76][54], and casimersen [77][55], generating slight improvements in life expectancy. The interactions of exon-skipping therapies with dietary supplements are largely unknown. One study observed co-administering Gly in mdx led to increased uptake of phosphorodiamidate morpholino oligomers in regenerating muscle fibers mediated through mTORC1 activation, resulting in functional improvement and a spectacular 50-fold increase in dystrophin expression in abdominal muscles [78][56]. In addition, intravenous supplementation with Gly 7 days prior to exogeneous muscle stem cell or primary myoblast transfer in mdx augmented the efficiency of transplantation, which was observed in the increased numbers of dystrophin-positive muscle fibers evaluated in the tibialis anterior after 3 weeks. A protocol for Gly-enhanced exon-skipping has recently been published [79][57]. Lower dosages of exon-skipping therapies could substantially reduce their cost and their risk of side effects. Another promising molecular approach is the transfer of a microdystrophin gene copy inserted in an adeno-associated virus (AAV) vector [80][58]. On 22 June this year, the U.S. Food and Drug Administration approved elevidys, the first gene therapy for the treatment of pediatric patients of 4 to 5 years of age. Gene replacement therapy for DMD is currently still mostly in the experimental phase, and the effects of amino acid supplementation on therapeutic efficiency have not been evaluated.

5. Adverse Effects and Human Clinical Trials

Amino acid supplements are commonly used by healthy individuals as well as patients. However, enhanced intake of amino acids is by no means risk-free, and may entail side effects, especially at high doses or after prolonged use [81][59]. Intravenous administration of amino acid supplements may cause more significant adverse effects when compared to oral or inhaled administration. For DMD, further research is necessary to determine which amino acid supplements are beneficial, and what their interactions with therapeutic interventions are. From studies in mdx mouse models, mild adverse effects have surfaced. The most notable side effects of reduction in weight and developmental delay appear to be dependent upon dose, route of administration, and study-specific conditions. For example, Tau in high doses was described to cause growth deficits [55][60] while lower doses did not [52][61], yet another study did not show deleterious effects with the same high dose of Tau [53][62]. Impaired body weight gain was also reported in NAC-treated young growing mdx [49][63]. NAC has been used for years for different medical indications, most particularly in respiratory medicine for treating chronic obstructive pulmonary disease, interstitial lung diseases, bronchiectasis, and infectious disease. Additionally, NAC is used as an antidote for paracetamol poisoning, and in psychiatric illnesses and addictive behaviors [82][64]. It is considered a “conditionally essential” amino acid by some because the synthesis of Cys may be compromised under the stress of illness or in preterm infants [11][8]. For chronic use, a maximum dose of 600 mg/day is maintained, with the main indication being chronic obstructive pulmonary disease. Most of the side effects related to the oral intake of NAC are associated with gastrointestinal symptoms and nausea. Interestingly, Arg supplements have been observed to alleviate gastrointestinal dysfunction in mdx [83][65]. In comparison to relatively abundant studies in the mdx model, few human trials have been attempted with amino acid supplements in DMD patients [10][66]. From the available evidence, researchers can conclude that some benefit of amino acid supplementation may be a general phenomenon, irrespective of specific formulae. For instance, in a randomized, double-blind study comparing an oral supplement of Gln (0.5 g/kg/day) to a nonspecific amino acid mixture (0.8 g/kg/day), the latter equally inhibited whole-body protein degradation in DMD [84][67]. However, a double-blind, randomized crossover trial with sequential intervention periods of 0.5 g/kg/day Gln and placebo for 4 months did not observe any clinical benefit [85][68]. Some other clinical trials have also generated disappointing results. A randomized, placebo-controlled study evaluating supplementation with the amino acid derivate creatine 5 g/day for 8 weeks and determining calf muscle phosphorus metabolite ratios, provided no evidence for the benefit of long-term treatment, nor did it observe an effect on DMD patient lifespan [86][69]. A double-blind, placebo-controlled clinical trial evaluating Gln (0.6 g/kg/day) and creatine (5 g/day) for 6 months found no statistically significant effect on muscle strength [87][70]. Another randomized clinical trial reported more promising results in ambulant DMD patients aged 6.5 to 10 years treated with a combination of 2.5 g L-citrulline and 0.25 g metformin three times a day for 26 weeks. A clinically relevant reduction in motor function decline was observed, with favorable effects reaching significance only in stable patients. Overall, treatment was well tolerated, with only mild adverse effects reported [88][71]. NAC has not been tested in DMD; however, a randomized double-blinded placebo-controlled trial was conducted in another genetic muscle disorder, i.e., ryanodine receptor 1-related myopathy. Oral NAC daily for 6 months (adults 2.7 g; children 30 mg/kg) did not lead to adverse events; however, therapeutic benefit was equally lacking, with no improvement in participants’ 6 min walk test distance and unchanged levels of oxidative stress [89][72]. No results of clinical trials of Tau supplementation have been reported for DMD either; however, studies in metabolic disorders have generated encouraging results. In type 2 diabetes mellitus patients on a low-calorie diet, placebo-controlled administration of 1 g Tau three times per day for 8 weeks lead to a considerable decrease in serum insulin, along with improvement in inflammatory and oxidative stress markers [90][73]. In an open-label, phase III trial in mitochondrial myopathy, 9 to 12 g Tau per day for 52 weeks effectively reduced the recurrence of stroke-like episodes in patients suffering from lactic acidosis and stroke-like episodes (MELAS) [91][74]. Additionally, clinical trials have already picked up on the positive effects of Tau on muscle function. For instance, in a double-blinded randomized clinical trial, patients with chronic liver disease receiving 2 g Tau per day as an oral supplement self-reported a significant reduction in the frequency, duration, and intensity of muscle cramps [92][75]. Tau supplementation may transcend therapeutic use in human disease. In healthy subjects, benefits of Tau supplementation on aerobic and anaerobic performance, muscle damage, metabolic stress, and recovery have been reviewed recently, concluding that evidence so far shows varied and mostly limited effects [93][76]. However, a placebo-controlled evaluation of single oral administration of 0.1 g/kg Tau before resistance training did observe a significant positive effect on exercise performance [94][77], and a meta-analysis of ten published studies concluded that Tau supplements of 1 to 6 g/day for 2 weeks did improve endurance performance [95][78]. Overall, Tau supplementation was well tolerated, as no severe adverse events have been reported. Of interest, Tau abundance decreases during aging, and a reversal of this decline through Tau supplementation has very recently been reported to increase health and/or life span in different species including monkeys [96][79].

References

  1. Szabo, S.M.; Salhany, R.M.; Deighton, A.; Harwood, M.; Mah, J.; Gooch, K.L. The clinical course of Duchenne muscular dystrophy in the corticosteroid treatment era: A systematic literature review. Orphanet J. Rare Dis. 2021, 16, 237.
  2. Duan, D.; Goemans, N.; Takeda, S.; Mercuri, E.; Artsma-Rus, A. Duchenne muscular dystrophy. Nat. Rev. Dis. Primers 2021, 7, 13.
  3. Kourakis, S.; Timpani, C.A.; Campelj, D.G.; Hafner, P.; Gueven, N.; Fischer, D.; Rybalka, E. Standard of care versus new-wave corticosteroids in the treatment of Duchenne muscular dystrophy: Can we do better? Orphanet J. Rare Dis. 2021, 16, e117.
  4. Cordova, G.; Negroni, E.; Cabello-Verrugio, C.; Mouly, V.; Trollet, C. Combined therapies for Duchenne muscular dystrophy to optimize treatment efficacy. Front. Genet. 2018, 9, 114.
  5. Grounds, M.D.; Radley, H.G.; Lynch, G.S.; Nagaraju, K.; De Luca, A. Towards developing standard operating procedures for pre-clinical testing in the mdx mouse model of Duchenne muscular dystrophy. Neurobiol. Dis. 2008, 31, 11–19.
  6. Davis, J.; Samuels, E.; Mullins, L. Nutrition considerations in Duchenne muscular dystrophy. Nutr. Clin. Pract. 2015, 30, 511–521.
  7. Davidson, Z.E.; Rodden, G.; Mázala, D.A.G.; Moore, C.; Papillon, C.; Hasemann, A.J.; Truby, H.; Grange, R.W. Practical Nutrition Guidelines for Individuals with Duchenne Muscular Dystrophy. In Regenerative Medicine for Degenerative Muscle Diseases; Childers, M., Ed.; Stem Cell Biology and Regenerative Medicine; Humana Press: New York, NY, USA, 2016; pp. 225–279. ISBN 978-1-4939-3227-6.
  8. Riedijk, M.A.; van Beek, R.H.; Voortman, G.; de Bie, H.M.; Dassel, A.C.; van Goudoever, J.B. Cysteine: A conditionally essential amino acid in low-birth-weight preterm infants? Am. J. Clin. Nutr. 2007, 86, 1120–1125.
  9. Terrill, J.R.; Huchet, C.; Le Guiner, C.; Lafoux, A.; Caudal, D.; Tulangekar, A.; Bryson-Richardson, R.J.; Sztal, T.E.; Grounds, M.D.; Arthur, P.G. Muscle pathology in dystrophic rats and zebrafish is unresponsive to taurine treatment, compared to the mdx mouse model for Duchenne muscular dystrophy. Metabolites 2023, 13, 232.
  10. Martins-Bach, A.B.; Bloise, A.C.; Vainzof, M.; Rabbani, S.R. Metabolic profile of dystrophic mdx mouse muscles analyzed with in vitro magnetic resonance spectroscopy (MRS). Magn. Reson. Imag. 2012, 30, 1167–1176.
  11. Panza, E.; Vellecco, V.; Iannotti, F.A.; Paris, D.; Manzo, O.L.; Smimmo, M.; Mitilini, N.; Boscaino, A.; de Dominicis, G.; Bucci, M.; et al. Duchenne’s muscular dystrophy involves a defective transsulfuration pathway activity. Redox Biol. 2021, 45, 102040.
  12. Terrill, J.R.; Grounds, M.D.; Arthur, P.G. Taurine deficiency, synthesis and transport in the mdx mouse model for Duchenne Muscular Dystrophy. Int. J. Biochem. Cell Biol. 2015, 66, 141–148.
  13. Culbertson, J.Y.; Kreider, R.B.; Greenwood, M.; Cooke, M. Effects of beta-alanine on muscle carnosine and exercise performance: A review of the current literature. Nutrients 2010, 2, 75–98.
  14. Lu, S.C. Regulation of glutathione synthesis. Mol. Asp. Med. 2009, 30, 42–59.
  15. Rapucci Moraes, L.H.; Constâncio Bollineli, R.; Sayuri Mizobuti, D.; Dos Reis Silveira, L.; Marques, M.J.; Minatel, E. Effect of N-acetylcysteine plus deferoxamine on oxidative stress and inflammation in dystrophic muscle cells. Redox Rep. 2015, 20, 109–115.
  16. Medved, I.; Brown, M.J.; Bjorksten, A.R.; Murphy, K.T.; Petersen, A.C.; Sostaric, S.; Gong, X.; McKenna, M.J. N-acetylcysteine enhances muscle cysteine and glutathione availability and attenuates fatigue during prolonged exercise in endurance-trained individuals. J. Appl. Physiol. 2004, 97, 1477–1485.
  17. Merckx, C.; De Paepe, B. The role of taurine in skeletal muscle functioning and its potential as a supportive treatment for Duchenne muscular dystrophy. Metabolites 2022, 12, 193.
  18. Lee, E.C.; Maresh, C.M.; Kraemer, W.J.; Yamamoto, L.M.; Hatfield, D.L.; Bailey, B.L.; Armstrong, L.E.; Volek, J.S.; McDermott, B.P.; As Craig, S. Ergogenic effects of betaine supplementation on strength and power performance. J. Int. Soc. Sports Nutr. 2010, 7, 27.
  19. Ueland, P.M. Choline and betaine in health and disease. J. Inherit. Metab. Dis. 2011, 34, 3–15.
  20. Hoffman, J.R.; Ratamess, N.A.; Kang, J.; Rashti, S.L.; Avery, D.; Faigenbaum, A.D. Effect of betaine supplementation on power performance and fatigue. J. Int. Soc. Sports Nutr. 2009, 6, 7.
  21. Hsieh, T.J.; Jaw, T.S.; Chuang, H.Y.; Jong, Y.J.; Liu, G.C.; Li, C.W. Muscle metabolism in Duchenne muscular dystrophy assessed by in vivo proton magnetic resonance spectroscopy. J. Comput. Assist. Tomogr. 2009, 33, 150–154.
  22. Graf, R.; Anzali, S.; Buenger, J.; Pfluecker, F.; Driller, H. The multifunctional role of ectoine as a natural cell protectant. Clin. Dermatol. 2008, 26, 326–333.
  23. Terrill, J.R.; Duong, M.N.; Turner, R.; Le Guiner, C.; Boyatzis, A.; Kettle, A.J.; Grounds, M.D.; Arthur, P.G. Levels of inflammation and oxidative stress, and a role for taurine in dystropathology of the Golden retriever muscular dystrophy dog model for Duchenne muscular dystrophy. Redox Biol. 2016, 9, 276–286.
  24. Terrill, J.R.; Boyatzis, A.; Grounds, M.D.; Arthur, P.G. Treatment with the cysteine precursor l-2-oxothiazolidine-4-carboxylate (OTC) implicates taurine deficiency in severity of dystropathology in mdx mice. Int. J. Biochem. Cell Biol. 2013, 45, 2097–2108.
  25. Stipanuk, M.H. Role of the liver in regulation of body cysteine and taurine levels: A brief review. Neurochem. Res. 2004, 29, 105–110.
  26. Barbiera, A.; Sorrentino, S.; Lepore, E.; Carfì, A.; Sica, G.; Dobrowolny, G.; Scicchitano, B.M. Taurine attenuates catabolic processes related to the onset of sarcopenia. Int. J. Mol. Sci. 2020, 21, 8865.
  27. Gupta, S.C.; Sundaram, C.; Reuter, S.; Aggarwal, B.B. Inhibiting NF-κB activation by small molecules as a therapeutic strategy. Biochim. Biophys. Acta 2010, 1799, 775–787.
  28. McGreevy, J.W.; Hakim, C.H.; McIntosh, M.A.; Duan, D. Animal models of Duchenne muscular dystrophy: From basic mechanisms to gene therapy. Dis. Model. Mech. 2015, 8, 195–213.
  29. Putten, M.; Putker, K.; Overzier, M.; Adamzek, W.A.; Pasteuning-Vuhman, S.; Plomp, J.J.; Aartsma-Rus, A. Natural disease history of the D2-mdx mouse model for Duchenne muscular dystrophy. FASEB J. 2019, 33, 8110–8124.
  30. Schultz, T.I.; Raucci, F.J.; Salloum, F.N. Cardiovascular disease in Duchenne muscular dystrophy: Overview and insight into novel therapeutic targets. JACC Basic. Transl. Sci. 2022, 7, 608–625.
  31. Dubinin, M.V.; Talanov, E.Y.; Tenkov, K.S.; Starinets, V.S.; Mikheeva, I.B.; Belosludtsev, K.N. Transport of Ca2+ and Ca2+-dependent permeability transition in heart mitochondria in the early stages of Duchenne muscular dystrophy. Biochim. Biophys. Acta 2020, 10, 2148250.
  32. Williams, I.A.; Allen, D.G. The role of reactive oxygen species in the hearts of dystrophin-deficient mdx mice. Am. J. Physiol. Heart Circ. Physiol. 2007, 293, H1969–H1977.
  33. Redwan, A.; Kiriaev, L.; Kueh, S.; Morley, J.W.; Peter Houweling, P.; Perry, B.D.; Head, S.I. Six weeks of N-acetylcysteine antioxidant in drinking water decreases pathological fiber branching in mdx mouse dystrophic fast-twitch skeletal muscle. Front. Physiol. 2023, 14, 1109587.
  34. Holeček, M. Branched-chain amino acids in health and disease: Metabolism, alterations in blood plasma, and as supplements. Nutr. Metab. 2018, 15, 33.
  35. White, J.P. Amino Acid Trafficking and Skeletal Muscle Protein Synthesis: A Case of Supply and Demand. Front. Cell Dev. Biol. 2021, 9, 656604.
  36. Dirks, M.; Wall, B.; van Loon, L.V. Interventional strategies to combat muscle disuse atrophy in humans: Focus on neuromuscular electrical stimulation and dietary protein. J. Appl. Physiol. 2018, 125, 850–861.
  37. Mantuano, P.; Boccanegra, B.; Bianchini, G.; Conte, E.; De Bellis, M.; Sanarica, F.; Camerino, G.M.; Pierno, S.; Cappellari, O.; Allegretti, M.; et al. BCAAs and Di-Alanine supplementation in the prevention of skeletal muscle atrophy: Preclinical evaluation in a murine model of hind limb unloading. Pharmacol. Res. 2021, 171, 105798.
  38. Banfi, S.; D’Antona, G.; Ruocco, C.; Meregalli, M.; Belicchi, M.; Bella, P.; Erratico, S.; Donato, E.; Rossi, F.; Bifari, F.; et al. Supplementation with a selective amino acid formula ameliorates muscular dystrophy in mdx mice. Sci. Rep. 2018, 8, 14659.
  39. Matthews, E.; Brassington, R.; Kuntzer, T.; Jichi, F.; Manzur, A.Y. Corticosteroids for the treatment of Duchenne muscular dystrophy. Cochrane Database Syst. Rev. 2016, 5, CD003725.
  40. Ruocco, C.; Ragni, M.; Rossi, F.; Carullo, P.; Ghini, V.; Piscitelli, F.; Cutignano, A.; Manzo, E.; Ioris, R.M.; Bontems, F.; et al. Manipulation of dietary amino acids prevents and reverses obesity in mice through multiple mechanisms that modulate energy homeostasis. Diabetes 2020, 69, 2324–2339.
  41. Okekunle, A.P.; Lee, H.; Provido, S.M.P.; Chung, G.H.; Hong, S.; Yu, S.H.; Lee, C.B.; Lee, J.E. Dietary branched-chain amino acids and odds of obesity among immigrant Filipino women: The Filipino women’s diet and health study (FiLWHEL). BMC Public Health 2022, 22, 654.
  42. De Bandt, J.P.; Coumoul, X.; Barouki, R. Branched-chain amino acids and insulin resistance, from protein supply to diet-induced obesity. Nutrients 2023, 15, 68.
  43. Zhang, H.; Xiang, L.; Huo, M.; Wu, Y.; Yu, M.; Lau, C.W.; Tian, D.; Gou, L.; Huang, Y.; Luo, J.Y.; et al. Branched-chain amino acid supplementation impairs insulin sensitivity and promotes lipogenesis during exercise in diet-induced obese mice. Obesity 2022, 30, 1205–1218.
  44. Ooi, D.S.Q.; Ling, J.Q.R.; Sadananthan, S.A.; Velan, S.S.; Ong, F.Y.; Khoo, C.M.; Tai, E.S.; Henry, C.J.; Leow, M.K.S.; Khoo, E.Y.H.; et al. Branched-chain amino acid supplementation does not preserve lean mass or affect metabolic profile in adults with overweight or obesity in a randomized controlled weight loss intervention. J. Nutr. 2021, 151, 911–920.
  45. Ammann, P.; Laib, A.; Bonjour, J.P.; Meyer, J.M.; Rüegsegger, P.; Rizzoli, R. Dietary essential amino acid supplements increase bone strength by influencing bone mass and bone microarchitecture in ovariectomized adult rats fed an isocaloric low-protein diet. J. Bone Min. Res. 2002, 17, 1264–1272.
  46. Panahi, N.; Fahimfar, N.; Roshani, S.; Arjmand, B.; Gharibzadeh, S.; Shafiee, G.; Migliavacca, E.; Breuille, D.; Feige, J.N.; Grzywinski, Y.; et al. Association of amino acid metabolites with osteoporosis, a metabolomic approach: Bushehr elderly health program. Metabolomics 2022, 18, 63.
  47. Su, Y.; Elshorbagy, A.; Turner, C.; Refsum, H.; Chan, R.; Kwok, T. Circulating amino acids are associated with bone mineral density decline and ten-year major osteoporotic fracture risk in older community-dwelling adults. Bone 2019, 129, 115082.
  48. Lv, Z.; Shi, W.; Zhang, Q. Role of essential amino acids in age-induced bone loss. Int. J. Mol. Sci. 2022, 23, 11281.
  49. Archer, J.D.; Vargas, C.C.; Anderson, J.E. Persistent and improved functional gain in mdx dystrophic mice after treatment with L-arginine and deflazacort. FASEB J. 2006, 20, 738–740.
  50. Ham, D.J.; Gardner, A.; Kennedy, T.L.; Trieu, J.; Naim, T.; Chee, A.; Alves, F.M.; Caldow, M.K.; Lynch, G.S.; Koopman, R. Glycine administration attenuates progression of dystrophic pathology in prednisolone-treated dystrophin/utrophin null mice. Sci. Rep. 2019, 9, 12982.
  51. Aartsma-Rus, A.; Straub, V.; Hemmings, R.; Haas, M.; Schlosser-Weber, G.; Stoyanova-Beninska, V.; Mercuri, E.; Muntoni, F.; Sepodes, B.; Vroom, E.; et al. Development of exon skipping therapies for Duchenne muscular dystrophy: A critical review and a perspective on the outstanding Issues. Nucleic Acid. Ther. 2017, 27, 251–259.
  52. Syed, Y.Y. Eteplirsen: First Global Approval. Drugs 2016, 76, 1699–1704.
  53. Heo, Y.A. Golodirsen: First approval. Drugs 2020, 80, 329–333.
  54. Dhillon, S. Viltolarsen: First approval. Drugs 2020, 80, 1027–1031.
  55. Shirley, M. Casimersen: First approval. Drugs 2021, 81, 875–879.
  56. Lin, C.; Han, G.; Ning, H.; Song, J.; Ran, N.; Yi, X.; Seow, Y.; Yin, H.F. Glycine enhances satellite cell proliferation, cell transplantation, and oligonucleotide efficacy in dystrophic muscle. Mol. Ther. 2020, 28, 1339–1358.
  57. Han, G.; Lin, C.; Yin, H.F. Use of glycine to augment exon skipping and cell therapies for Duchenne muscular dystrophy. Methods Mol. Biol. 2023, 2587, 165–182.
  58. Elangkovan, N.; Dickson, G. Gene therapy for Duchenne muscular dystrophy. J. Neuromuscul. Dis. 2021, 8 (Suppl. S2), S303–S316.
  59. Holeček, M. Side effects of amino acid supplements. Physiol. Res. 2022, 71, 29–45.
  60. Terrill, J.R.; Pinniger, G.J.; Nair, K.V.; Grounds, M.D.; Arthur, P.G. Beneficial effects of high dose taurine treatment in juvenile dystrophic mdx mice are offset by growth restriction. PLoS ONE 2017, 12, e0187317.
  61. Terrill, J.R.; Pinniger, G.J.; Graves, J.A.; Grounds, M.D.; Arthur, P.G. Increasing taurine intake and taurine synthesis improves skeletal muscle function in the mdx mouse model for Duchenne muscular dystrophy. J. Physiol. 2016, 594, 3095–3110.
  62. De Luca, A.; Pierno, S.; Liantonio, A.; Cetrone, M.; Camerino, C.; Fraysse, B.; Mirabella, M.; Servidei, S.; Rüegg, U.T.; Conte Camerino, D. Enhanced dystrophic progression in mdx mice by exercise and beneficial effects of taurine and insulin-like growth factor-1. J. Pharmacol. Exp. Ther. 2003, 304, 453–463.
  63. Pinniger, G.J.; Terrill, J.R.; Assan, E.B.; Grounds, M.D.; Arthur, P.G. Pre-clinical evaluation of N-acetylcysteine reveals side effects in the mdx mouse model of Duchenne muscular dystrophy. J. Physiol. 2017, 595, 7093–7107.
  64. Calverley, P.; Rogliani, P.; Papi, A. Safety of N-acetylcysteine at high doses in chronic respiratory diseases: A review. Drug Saf. 2021, 44, 273–290.
  65. Swiderski, K.; Bindon, R.; Trieu, J.; Naim, T.; Schokman, S.; Swaminathan, M.; Leembruggen, A.J.L.; Hill-Yardin, E.L.; Koopman, R.; Bornstein, J.C.; et al. Spatiotemporal mapping reveals regional gastrointestinal dysfunction in mdx dystrophic mice ameliorated by oral L-arginine supplementation. J. Neurogastroenterol. Motil. 2020, 26, 133–146.
  66. Boccanegra, B.; Verhaart, I.E.C.; Cappellari, O.; Vroom, E.; De Luca, A. Safety issues and harmful pharmacological interactions of nutritional supplements in Duchenne muscular dystrophy: Considerations for Standard of Care and emerging virus outbreaks. Pharmacol. Res. 2020, 158, 104917.
  67. Mok, E.; Eléouet-Da Violante, C.; Daubrosse, C.; Gottrand, F.; Rigal, O.; Fontan, J.E.; Cuisset, J.M.; Guilhot, J.; Hankard, R. Oral glutamine and amino acid supplementation inhibit whole-body protein degradation in children with Duchenne muscular dystrophy. Am. J. Clin. Nutr. 2006, 83, 823–828.
  68. Mok, E.; Letellier, G.; Cuisset, J.M.; Denjean, A.; Gottrand, F.; Alberti, C.; Hankard, R. Lack of functional benefit with glutamine versus placebo in Duchenne muscular dystrophy: A randomized crossover trial. PLoS ONE 2009, 4, e5448.
  69. Banerjee, B.; Sharma, U.; Balasubramanian, K.; Kalaivani, M.; Kalra, V.; Jagannathan, N.R. Effect of creatine monohydrate in improving cellular energetics and muscle strength in ambulatory Duchenne muscular dystrophy patients: A randomized, placebo-controlled 31P MRS study. Magn. Reson. Imaging 2010, 28, 698–707.
  70. Escolar, D.M.; Buyse, G.; Henricson, E.; Leshner, R.; Florence, J.; Mayhew, J.; Tesi-Rocha, C.; Gorni, K.; Pasquali, L.; Patel, K.M.; et al. CINRG randomized controlled trial of creatine and glutamine in Duchenne muscular dystrophy. Ann. Neurol. 2005, 58, 151–155.
  71. Hafner, P.; Bonati, U.; Klein, A.; Rubino, D.; Gocheva, V.; Schmidt, S.; Schroeder, J.; Bernert, G.; Laugel, V.; Steinlin, M.; et al. Effect of combination L-Citrulline and metformin treatment on motor function in patients with Duchenne muscular dystrophy: A randomized clinical trial. JAMA Netw. Open 2019, 2, e1914171.
  72. Todd, J.J.; Lawal, T.A.; Witherspoon, J.W.; Chrismer, I.C.; Razaqyar, M.S.; Punjabi, M.; Elliott, J.S.; Tounkara, F.; Kuo, A.; Shelton, M.O.; et al. Randomized controlled trial of N-acetylcysteine therapy for RYR1-related myopathies. Neurology 2020, 94, e1434–e1444.
  73. Moludi, J.; Qaisar, S.A.; Kadhim, M.M.; Ahmadi, Y.; Davari, M. Protective and therapeutic effectiveness of taurine supplementation plus low calorie diet on metabolic parameters and endothelial markers in patients with diabetes mellitus: A randomized, clinical trial. Nutr. Metab. 2022, 19, 49.
  74. Ohsawa, Y.; Hagiwara, H.; Nishimatsu, S.I.; Hirakawa, A.; Kamimura, N.; Ohtsubo, H.; Fukai, Y.; Murakami, T.; Koga, Y.; Goto, Y.I.; et al. Taurine supplementation for prevention of stroke-like episodes in MELAS: A multicentre, open-label, 52-week phase III trial. J. Neurol. Neurosurg. Psychiatry 2019, 90, 529–536.
  75. Vidot, H.; Cvejic, E.; Carey, S.; Strasser, S.I.; McCaughan, G.W.; Allman-Farinelli, M.; Shackel, N.A. Randomised clinical trial: Oral taurine supplementation versus placebo reduces muscle cramps in patients with chronic liver disease. Aliment. Pharmacol. Ther. 2018, 48, 704–712.
  76. Kurtz, J.A.; VanDusseldorp, T.A.; Doyle, J.A.; Otis, J.S. Taurine in sports and exercise. J. Int. Soc. Sports Nutr. 2021, 18, 39.
  77. Akalp, K.; Vatansever, Ş.; Sönmez, G.T. Effects of acute taurine consumption on single bout of muscular endurance resistance exercise performance and recovery in resistance trained young male adults. Biomed. Hum. Kinet. 2023, 15, 74–82.
  78. Waldron, M.; Patterson, S.D.; Tallent, J.; Jeffries, O. The effects of an oral taurine dose and supplementation period on endurance exercise performance in humans: A meta-analysis. Sports Med. 2018, 48, 1247–1253.
  79. Singh, P.; Gollapalli, K.; Mangiola, S.; Schranner, D.; Aslam Yusuf, M.; Chamoli, M.; Shi, S.L.; Lopes Bastos, B.; Nair, T.; Riermeier, A.; et al. Taurine deficiency as a driver of aging. Science 2023, 380, eabn9257.
More
© Text is available under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/)
Video Production Service
Feedback