Encyclopedia
Please note this is a comparison between Version 1 by Viviana Moresi and Version 2 by Jason Zhu.
Neurogenic muscle atrophy is a debilitating condition that occurs from nerve trauma in association with diseases or during aging, leading to reduced interaction between motoneurons and skeletal fibers. Therapeutic approaches aiming at preserving muscle mass in a scenario of decreased nervous input include physical activity and employment of drugs that slow down the progression of the condition yet provide no concrete resolution. Nutritional support appears as a precious tool, adding to the success of personalized medicine, and could thus play a relevant part in mitigating neurogenic muscle atrophy.
- nutraceuticals
- natural compounds
- muscle wasting
1. Introduction
Functional foods are considered as either fresh or processed foods that naturally promote health and prevent or ameliorate diseases beyond their basic nutritional functions [1][85]. Functional foods or ingredients with protective, therapeutic outcomes against neurogenic muscle atrophy have recently received increasing consideration, being suitable for long-term treatment and potentially free from side effects.
2. Protein or Amino Acids
High daily protein intake (1.0–1.2 g/kg/day) correlates with the maintenance of muscle mass with aging [2][86]. Such assumption persists even though contrasting data were reported from randomized clinical trials employing protein or amino acid supplements [3][4][5][6][7][87,88,89,90,91], probably due to the heterogeneity of the initial populations and to the difficulty in measuring the effective protein intake throughout the studies. Similarly, a positive correlation has been found between the length of survival of ALS patients and the amount of protein consumed, especially at the early stage of the disease [8][92]. However, dietary supplementation with creatine or amino acids has not been proven to be effective in improving the prognosis of ALS patients [9][93].
When the studies are stratified by the specific amino acids used, the most interesting results are the following:
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Branched-chain amino acids (BCAAs), i.e., leucine, isoleucine, and valine, are three of the nine essential amino acids and are found in protein-rich foods such as eggs, meat, and dairy products. A BCAA-enriched diet has been shown to be protective against sarcopenia in both slow and fast muscles of old mice [10][94] and in elderly subjects [5][11][12][89,95,96], by promoting mitochondrial genesis, thus improving muscle endurance, and decreasing oxidative stress. In contrast, treatment of ALS patients with BCAAs or L-threonine for six months failed to show beneficial effects on disease progression [13][97].
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Leucine is an essential BCAA present in all protein-rich foods, but is more abundant in those of animal origin [14][98]. A leucine-enriched exclusive diet prevented neurogenic muscle atrophy in denervated rat soleus (slow) muscle, by increasing the AKT/mTOR anabolic pathway and decreasing the AMPK-catabolic one [15][99]. Leucine supplementation is potentially useful to increase protein synthesis for counteracting muscle sarcopenia in elderly subjects [16][17][100,101].
As for the mechanism underlying their beneficial effects, the dietary intake of essential amino acids increases the expression of several miRNAs in the skeletal muscle, including miR-1, miR-23a, miR-208b, miR-499, and miR-27a, regulating the expression of muscle-specific growth-related genes and thereby promoting muscle mass [18][19][102,103].
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Beta-Hydroxy-Beta-Methyl Butyrate (HMB) is a natural metabolite of the amino acid leucine, and is found in small quantities in grapefruit, alfalfa, and catfish. In humans, 2–10% of dietary L-leucine is converted to HMB, corresponding to about 0.3 g/day; however, when taken as a supplement the doses are 10–20-fold higher [20][104]. As a derivate of a BCAA, HMB is thought to act as pro-anabolic and anti-catabolic compound for skeletal muscle, and early studies showed a positive impact of HMB supplementation in counteracting the age-related losses of skeletal muscle mass in elderly subjects [21][22][23][105,106,107]. However, two recent articles published opposite results: according to a review, the current evidence is inconclusive with regard to any positive effects of HMB supplementation on functional outcome measurements or muscle mass in elderly human subjects and in hospitalized patients [24][108], while a meta-analysis concluded that HMB supplementation helps increase muscle strength in elderly people [25][109].
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Creatine is a compound derived from glycine and arginine which is mostly present in skeletal muscle, where it is used as an energy store, and can be found in red meat and seafood. Abundant evidence indicates that creatine supplementation increases skeletal muscle mass and strength if associated with resistance training [26][110], due to its beneficial effects on decreasing muscle protein breakdown, inflammation, and oxidative stress; interestingly, this also holds true with aging [27][28][111,112]. Despite the positive effects on skeletal muscle homeostasis, current literature suggests that exogenous creatine supplementation appears to be poorly effective in treating ALS [29][30][113,114].
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Carnitine is a quaternary ammonium compound required for the transport of long-chain fatty acids into mitochondria for energy production. Carnitine can be mainly found in animal products such as meat, fish, poultry, and milk, and is involved in skeletal muscle protein homeostasis by regulating both protein synthesis and breakdown, being an antioxidant and anti-inflammatory compound [31][115]. Interestingly, denervation and aging decrease carnitine levels in both slow and fast rat skeletal muscles [32][116], suggesting a causative role for carnitine in the atrophic program. Carnitine supplementation, alone or in combination with physical exercise, counteracts the age-dependent decline of mitochondrial function in the soleus rat muscle, improving muscle energy production and body protein mass [33][34][35][117,118,119]. The positive effects of carnitine supplementation were also reported in a murine model of ALS [36][120], as well as in a phase II clinical trial [37][121], proving to be effective in slowing down the progression of muscle weakness and prolonging mouse and patient survival.
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Carnosine is a dipeptide composed of the beta-alanine and histidine amino acids and mainly present in meats. Carnosine exerts numerous positive actions in skeletal muscle, including antioxidant and antiglycation activity, enhanced calcium sensitivity, and H+ buffering [38][122] that may affect muscle performance and maintenance in aging and neuromuscular diseases [39][40][41][123,124,125]. In elderly subjects, an increase in carnosine intake counteracted cognitive decline and improved physical capacity, probably due to its anti-inflammatory action [42][43][126,127]. Further studies are needed to clarify the effects of carnosine supplementation on skeletal muscle proteolysis and synthesis in a denervation-dependent condition such as in aging or ALS.
3. Lipids
Unsaturated fatty acids have been reported to protect against muscle wasting in response to various pathological conditions. In particular, the replacement of saturated fatty acids (SFAs) by either mono- (MUFAs) or poly-unsaturated (PUFAs) has been associated with a lower sarcopenia risk score in a regression analysis that involved almost a thousand participants [44][129].
Several possible signaling pathways activated by PUFAs may underpin the beneficial effects on counteracting neurogenic muscle atrophy. Indeed, PUFAs exert a well-recognized anti-inflammatory action, increase nerve conduction, improve mitochondrial function, and stimulate muscle protein synthesis [45][46][133,134] while modulating autophagy and countering protein degradation [2][47][86,135].
Another aspect to which omega-3-fatty-acids may contribute to mitigation of atrophy is by beneficially modulating neuromuscular function, playing a suggested role on both the nerve and on the muscle fiber, altering membrane fluidity and sensitivity to acetylcholine (reviewed by [48][142]).
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Medium-chain triglycerides (MCT) are six-twelve carbon fatty acid esters of glycerol that can be found in coconut oil and products, palm oil, and dairy products. In mice, an MCT-enriched diet triggers glucose and lipid metabolism pathways and mitochondrial biogenesis in the skeletal muscle, thus improving muscle function under high-temperature conditions [49][143]. MCTs alone, or in combination with leucine and vitamin D, increase muscle strength and function in elderly adults [50][144[51],145]. However, MCT administration is detrimental for the heart of healthy or dystrophic mice [52][53][146,147]. Thus, careful examination of the systemic effects of MCT administration is encouraged in clinical studies.
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Alkylresorcinols (ARs), differently from PUFA, are amphiphilic phenolic lipids present in many kinds of cereals. Interestingly, AR dietary supplementation prevented neurogenic muscle atrophy in mice by affecting the autophagic pathway and thereby the lipid metabolism, but not the UPS activation [54][148]. This finding is intriguing, confirming that challenging metabolism may be an efficient therapeutic approach for maintaining muscle homeostasis, as suggested in ALS [55][149] and already described in other muscle pathologies [56][57][58][35,150,151].
4. Vitamins
Vitamins are essential micronutrients that cannot be synthesized by the organism, therefore, they must be obtained via the diet. Vitamins prevent skeletal muscle atrophy mainly for their anti-inflammatory properties and by buffering oxidative stress, thus affecting both protein synthesis and catabolism [59][152]. As for neurogenic muscle atrophy, however, uncertain findings have been reported on the effectiveness of vitamin supplementation.
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β-carotene is a red-orange pigment found in fruits and vegetables. The human body converts β-carotene into vitamin A. β-carotene attenuates ROS-dependent muscle atrophy in C2C12 myotubes by repressing the activation of atrogin-1 and MuRF1 [60][153]. In the elderly, high plasma concentrations of β-carotene and other similar antioxidants correlate with preserved muscle function [61][154], which would support their clinical use. However, weak data were reported about the effectiveness against neurogenic muscle atrophy in vivo, as β-carotene supplementation is only effective at the early stage of soleus muscle atrophy upon denervation [62][155].
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As for vitamin C, both dietary and circulating levels positively correlate with skeletal muscle mass measurements in middle- and older-aged subjects, suggesting that dietary vitamin C intake may be protective against sarcopenia [63][156]. Coherently, mice with defective vitamin C biosynthesis (SMP30-knockout mice) develop muscle atrophy in both fast and slow muscles, with high expression of muscle-specific E3-ubiquitin ligases, atrogin-1 and MuRF1, and high levels of ROS. Vitamin C supplementation was able to recover the SMP30-knockout muscle atrophy phenotype [64][157], highlighting its direct involvement in the maintenance of skeletal muscle homeostasis.
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Vitamin D certainly plays an important role in skeletal muscle physiology. Vitamin D deficiency in humans leads to muscle weakness and myalgia that can be reverted by vitamin D replenishment [65][158]. Vitamin D supplementation is associated with a significant increase in muscle mass and function in older adults with sarcopenia, especially for those with a significant baseline vitamin D deficiency [66][67][68][69][159,160,161,162]. At the molecular levels, skeletal muscle seems to express the vitamin D receptor, which mediates vitamin D-dependent signaling affecting calcium handling [70][163]. In addition to beneficial effects on age-related sarcopenia (revised in [71][164]), vitamin D helps muscle recovery following strenuous muscular activity. However, when vitamin D was supplemented in ALS, negative results prevailed over beneficial findings [72][73][74][75][165,166,167,168].
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Trolox, the cell-permeable derivative of vitamin E, was not able to exert any protective effects on neurogenic muscle atrophy in mice [76][62], despite evidence that the combined supplementation of whey protein, vitamin D and E can significantly improve muscle mass, strength, and markers of protein anabolism in sarcopenic subjects [77][169]. Two studies acknowledged the importance of oxidative stress in neurogenic muscle atrophy: the divergent conclusions come from different treatments (single or combined) and different models (mice vs. humans).
5. Plant-Derived Ingredients
Several plant-derived ingredients prevent or reduce muscle atrophy, especially by inhibiting muscle protein degradation while enhancing muscle synthesis, and/or exerting anti-inflammatory and anti-oxidative functions [78][79][171,172].
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Geranylgeraniol (GGOH), is a plant-derived isoprenoid with some beneficial effects for skeletal muscle mass. GGOH administration reduced the loss of myofiber size upon denervation in rat gastrocnemius muscle by affecting the expression of atrogin-1 [80][173], without enhancing muscle growth, even though it had previously shown a positive effect on C2C12 myoblast differentiation in vitro [81][174]. In addition, GGOH may interfere with the NF-κB and/or testosterone signaling in skeletal muscle, as demonstrated in other cell types [81][82][174,175], thus contributing to the protection against neurogenic muscle atrophy.
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Capsaicin is a chili pepper-derived extract with analgesic properties. Its protective action against neurogenic muscle atrophy has been described in a study [83][176]. Capsaicin administration, used as an agonist of the transient receptor potential cation channel, subfamily V, member 1 (TRPV1), induced muscle hypertrophy and alleviated denervation-induced atrophy in both fast and slow murine muscles. Activated TRPV1 increased intracellular Ca2+ concentration leading to mTOR activation and muscle biosynthesis [83][176].
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Polyphenols are a wide group of plant-derived organic compounds found in fruits, vegetables, coffee, tea, and whole grains. They are believed to be potential therapeutic agents for inhibiting muscle atrophy and improving muscle mass and strength [79][172]. Polyphenols act primarily as antioxidants and anti-inflammatory agents, thus inhibiting muscle atrophy-related genes and promoting the activation of the IGF-1 signaling pathway [79][84][172,177]. In addition, in vitro and in vivo observations proved the neuroprotective effects of these bioactive compounds by improving mitochondrial biogenesis and function, reducing toxic protein aggregates and microglia and astrocytes inflammation, and overall favoring motor neuron survival [85][178]. Some examples are reported below.
Isoflavones are a type of polyphenol mainly found in legumes, such as soybeans and other fruits and nuts. The administration of isoflavones has been shown to counteract TNF-α-induced C2C12 myotube atrophy by reducing MuRF1 promoter activity, and to prevent neurogenic muscle atrophy in vivo, when mice were pre-treated with isoflavones before denervation, mainly by interfering with apoptosis-dependent signaling [86][87][179,180].
Curcumin is extracted from the rhizome of turmeric, from the ginger family of plants, and displays anti-aging properties [88][181], by increasing the activity of SOD enzyme and increasing lifespan [89][182]. Accordingly, curcumin counteracts sarcopenia in mice [90][183], and clinical trials with healthy elderly subjects are ongoing [91][184]. Since curcumin is an antioxidant, as also reported above [92][185], it would be an ideal candidate as a nutraceutical for ALS and other neurodegenerative diseases. Indeed, a curcumin derivative, GT863, has been proven to slower motor dysfunction in a murine model of ALS [93][186]. In a different study exploiting the same SOD1 model, curcumin reduced the cytotoxicity of the amylogenic pathway [94][187]. Interestingly, curcumin protects the peripheral nervous system after injury [95][188] and promotes nerve regeneration [96][189]. The clinical use of curcumin in neurological disorders has been reviewed recently [97][190].
Resveratrol is a polyphenol found in grapes, red wine, and berries. It has been shown to inhibit protein degradation and protect skeletal muscle against atrophy in different in vivo models, including cancer, diabetes, chronic kidney disease, and disuse [98][99][100][101][191,192,193,194]. Dietary resveratrol supplementation prevented neurogenic muscle atrophy in mice, likely by interfering with the activation of UPS and autophagic pathways [102][195], in addition to its neuroprotective functions [103][196]. Moreover, resveratrol affects muscle mass by promoting muscle cell differentiation and PGC-1α activation through the concomitant up-regulation of miR-21 and miR27-b and downregulation of miR-133b, miR-30b, and miR-149 [104][197]. Convincing data on the effects of resveratrol on muscle mass in experimental models of neurodegenerative diseases are still missing.
Avenanthramides (AVNs), also known as N-cinnamoylanthranilate alkaloids or anthranilic acid amides, are a group of low molecular weight phenolic amides found mainly in the whole grain oat [105][198]. AVNs are effective in inhibiting NF-kB activation, ROS production, and proinflammatory cytokine expression in several cell types, including muscle cells [106][107][108][199,200,201]. In particular, AVNs bind and inhibit IKKβ activity, thereby inhibiting the NFκB-mediated inflammatory response in muscle cells [109][202] and TNF-α-induced myotube atrophy [106][199].
Among polyphenolic compounds, flavonoids are a subgroup generally having a 15-carbon skeleton. Both polyphenols and flavonoids exert anti-inflammatory and antioxidant actions and some flavonoids have been reported to possess protective functions, specifically with regard to neurogenic muscle atrophy.
Quercetin is a flavonoid found in many fruits and vegetables, such as in red wine, onions, green tea, apples, and berries. Quercetin has been shown to play protective functions against the muscle wasting that accompanies a variety of conditions. Regarding neurogenic muscle atrophy, quercetin suppresses TNF-α-induced C2C12 myotube atrophy by interfering with the activation of NF-κB and the consequent activation of the ubiquitin ligases atrogin-1 and MuRF-1, and by activating the Heme Oxygenase 1 (HO-1) [110][203]. Moreover, the administration of quercetin before denervating mice prevents neurogenic muscle atrophy by increasing mitochondriogenesis and function via PGC-1α [111][204].
Epicatechin is one of the most abundant flavonoids present in different fruits and green tea. Dietary supplementation of epicatechin prevents muscle loss in sarcopenic mice by increasing the expression of the myogenic marker MyoD and the antioxidant stress-related enzymes SOD and catalase, while reducing the expression of the catabolic marker genes, such as FoxO3a, myostatin, and MuRF1 [112][205]. Similarly, dietary supplementation with another green tea polyphenol, i.e., epigallocatechin-3-gallate, increases skeletal muscle mass and size in aged rats by downregulating the expression of the E3-ubiquitin ligases, MuRF1 and atrogin-1, and myostatin, and by increasing IGF-1 [113][206].
Apigenin is a flavonoid found in plants such as parsley, celery, and grapefruit. An apigenin-supplemented diet was able to prevent neurogenic muscle atrophy in both fast and slow murine muscles by inhibiting denervation-induced MuRF1 and IL-6 expression, thus affecting the activation of UPS and inflammatory processes within the muscle [114][207].
Genistein is a flavonoid derived from legumes. Dietary genistein supplementation attenuated the denervation-induced muscle atrophy in slow muscles in mice by interfering with the estrogen receptor-mediated activation of MuRF1 and atrogin1 expression [115][208].
8-prenylnaringenin is a prenylated flavonoid found in hops. Dietary ingestion of 8-prenylnaringenin prevents neurogenic muscle atrophy in mouse gastrocnemius muscles by stimulating the activation of Akt phosphorylation and preventing the induction of the key ubiquitin ligase involved in muscle atrophy atrogin-1 [116][209].
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Tomatidine is the metabolite obtained from α-tomatine, a glycoalkaloid abundantly present in tomato plants. Strikingly, the mRNA expression signature of tomatidine negatively correlates to that one of skeletal muscle atrophy upon fasting and spinal cord injury [117][210], suggesting that tomatidine might exert an anti-atrophic effect on skeletal muscle. Indeed, tomatine administration induced functional muscle hypertrophy, both in vitro and in vivo, accompanied by reduced adiposity, by activating mTORC1 signaling [117][210]. By enhancing protein synthesis and mitochondriogenesis, tomatidine also prevented muscle atrophy induced by fasting or immobilization in mice [117][210]. In C. elegans, tomatidine improves muscle function during aging by activating mitophagy and antioxidant cellular defenses [118][211]. Based on these promising findings, the use of tomatidine to counteract neurogenic muscle atrophy should be further investigated, along with the delineation of the molecular mechanisms underpinning the atrophy rescue.
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Tinospora cordifolia is a plant found in tropical and sub-tropical parts of Asia, Africa, and Australia, whose extract (TCE) has been widely used in ancient Ayurvedic and Tibetan medicine due to its high antioxidant activity [119][212]. TCE supplementation prevented neurogenic muscle atrophy by enhancing protein synthesis by antagonizing the proteolytic pathways (calpain and UPS), and by enhancing the oxidative stress response in both slow and fast mouse muscles [120][213].
6. Prebiotics, Probiotics and Dietary Fibers
Skeletal muscle wasting conditions, in addition to aging, deeply affect the intestinal mucosa [124][218] and are associated to changes in the gut biota [125][126][219,220]. Vice-versa, the gut microbiota can potentially affect skeletal muscle mass by modulating systemic inflammation and immunity, energy metabolism, and insulin sensitivity [127][221]. The importance of gut microbiota for the maintenance of skeletal muscle physiology and homeostasis has been recently demonstrated by comparing germ-free and pathogen-free mice [128][222]. The former, lacking a gut microbiota, showed skeletal muscle atrophy with clear molecular signs of muscle denervation, a phenotype that was reversed by transplanting the gut microbiota of the pathogen-free mice. Transplantation of the gut microbiota from pathogen-free mice into germ-free mice affects both slow and fast muscles, reducing the skeletal muscle atrophy markers atrogin-1 and MuRF1, and increasing mitochondriogenesis and oxidative metabolism, thus restoring skeletal muscle mass [128][222]. Additional studies have directly or indirectly proved a certain relationship between muscle mass and gut microbiota [129][130][131][223,224,225]. Although the pre and probiotics’ mechanisms for rescuing muscle mass are not yet well defined, gut microbiota may potentially influence muscles via endocrine and insulin sensitivity, energy metabolism, immunity, and inflammation [132][226]. Microbiota composition can be modified with the diet by increasing the consumption of prebiotics, i.e., non-digestible carbohydrates fermented in the lower part of the gut that stimulates the growth and/or activity(ies) of bacteria, or probiotics, i.e., live microorganisms, thus conferring a health benefit on the host. Often prebiotics have pleiotropic effects, regulating metabolism while acting on fat tissue and lean mass [133][227].
Since a dietary intervention alters the gut microbiota, it may be used as a potent tool to heal elderly subjects [134][228]. Indeed, dietary fiber administration is protective against age-related muscle loss by improving glucose metabolism, muscle function and lean body mass in adult subjects [135][136][229,230]. Such positive effects on skeletal muscle maintenance are attributed to dietary fiber’s ability to rapidly and reproducibly change the composition of microbiota, i.e., living members forming the microbiome, and microbiome, i.e., all of the genetic material within a microbiota [137][138][139][231,232,233]. For example, high dietary fiber intake increases the gut microbiota production of short-chain fatty acids [137][231], which are important regulators of skeletal muscle mass, metabolism, and function [140][234]. Beneficial effects of fiber supplementation have also been reported in metabolic disease conditions due to the decrease of insulin resistance [141][142][235,236] and pro-inflammatory cytokine concentration [143][144][237,238], which are two mechanisms directly involved in sarcopenia. In keeping with the approach of affecting microbiota, the administration of a prebiotic composed of a mixture of inulin and fructooligosaccharides for 13 weeks increased some skeletal muscle functional parameters in a randomized controlled double-blind study in elderly people [145][239].
Similarly to aging, the gut microbiota varies between ALS patients and healthy subjects; moreover, it changes further during the progression of the disease, with a decrease of potentially protective microbial groups, such as Bacteroidetes, and an increase of those groups with potential neurotoxic or pro-inflammatory activity, such as Cyanobacteria [146][240]. Supplementation with a probiotic formulation, consisting of a mixture of five lactic acid bacteria, for 6 months, despite regulating the intestinal microbiota of patients, did not influence the progression of the disease, as evaluated by ALS Functional Rating Scale–Revised (ALSFRS-R) score [146][240].
