Mechanisms Linking the Gut-Muscle Axis With Muscle Protein Metabolism and Anabolic Resistance: Implications for Older Adults at Risk of Sarcopenia

Abstract

Aging is associated with a decline in skeletal muscle mass and function—termed sarcopenia—as mediated, in part, by muscle anabolic resistance. This metabolic phenomenon describes the impaired response of muscle protein synthesis (MPS) to the provision of dietary amino acids and practice of resistance-based exercise. Recent observations highlight the gut-muscle axis as a physiological target for combatting anabolic resistance and reducing risk of sarcopenia. Experimental studies, primarily conducted in animal models of aging, suggest a mechanistic link between the gut microbiota and muscle atrophy, mediated via the modulation of systemic amino acid availability and low-grade inflammation that are both physiological factors known to underpin anabolic resistance. Moreover, in vivo and in vitro studies demonstrate the action of specific gut bacteria (Lactobacillus and Bifidobacterium) to increase systemic amino acid availability and elicit an anti-inflammatory response in the intestinal lumen. Prospective lifestyle approaches that target the gut-muscle axis have recently been examined in the context of mitigating sarcopenia risk. These approaches include increasing dietary fiber intake that promotes the growth and development of gut bacteria, thus enhancing the production of short-chain fatty acids (SCFA) (acetate, propionate, and butyrate). Prebiotic/probiotic/symbiotic supplementation also generates SCFA and may mitigate low-grade inflammation in older adults via modulation of the gut microbiota. Preliminary evidence also highlights the role of exercise in increasing the production of SCFA. Accordingly, lifestyle approaches that combine diets rich in fiber and probiotic supplementation with exercise training may serve to produce SCFA and increase microbial diversity, and thus may target the gut-muscle axis in mitigating anabolic resistance in older adults. Future mechanistic studies are warranted to establish the direct physiological action of distinct gut microbiota phenotypes on amino acid utilization and the postprandial stimulation of muscle protein synthesis in older adults.

Muscle Wasting in Chronic Kidney Disease: Mechanism and Clinical Implications—A Narrative Review

“…These results indicate that catabolic conditions in CKD induce an imbalance between these two closely interacting pathways, leading to an accelerated rate of muscle wasting [ 26 , 27 ]. Recently, a growing body of evidence has focused on the involvement of microRNAs (miRNAs) [ 28 , 29 , 30 ] and gut microbiota [ 31 , 32 , 33 ] in muscle wasting. Alterations in miRNA expression in CKD can lead to abnormal protein metabolism and muscle regeneration through the modulatory effects of miRNAs on relevant intracellular signaling pathways [ 22 ].…”

“…Accumulating evidence has shown that gut microbiota dysbiosis can be associated with various diseases apart from localized gastrointestinal illnesses, including cardiovascular, metabolic, hepatic, respiratory, neurologic, and oncologic disorders [ 33 , 77 ]. Consequently, the concept of the gut-muscle axis has been proposed to describe the remote effects of gut microbiota-derived metabolites on muscle metabolism [ 31 , 32 , 33 ]. The causal relationship between gut dysbiosis and muscle wasting is mediated by the reduced bioavailability of dietary amino acids, chronic systemic inflammation, insulin resistance, mitochondrial dysfunction, and modulation of host gene expression [ 31 , 32 , 33 , 80 ].…”

“…Consequently, the concept of the gut-muscle axis has been proposed to describe the remote effects of gut microbiota-derived metabolites on muscle metabolism [ 31 , 32 , 33 ]. The causal relationship between gut dysbiosis and muscle wasting is mediated by the reduced bioavailability of dietary amino acids, chronic systemic inflammation, insulin resistance, mitochondrial dysfunction, and modulation of host gene expression [ 31 , 32 , 33 , 80 ]. Animal studies have uncovered potential molecular pathways, including activation of PI3K-Akt, Toll-like receptor (TLRs)-NF-kB, MAPKs, and AMPK pathways, inducing upregulation of atrogin-1 and MuRF-1 by microbiota-derived metabolites, such as lipopolysaccharides and indoxyl sulfate, through gut barrier breakdown [ 81 , 82 ].…”

Anti-inflammatory Streptococcus thermophilus CNRZ160 limits sarcopenia induced by low-grade inflammation in older adult rats

“…However, it could be strongly suspected by the study of Fransen et al ( 17 ) who showed that microbiota transfer from elderly mice to axenic young mice stimulated immune pathways in the gut with bacterial components found in systemic circulation of the recipient mice capable to generate low-grade inflammation (NFκB pathway). Hence, we can speculate the existence of a gut-microbiota-muscle axis that could be also one of the determinant responsible for sarcopenia development during aging ( 18 , 19 ).…”

Lactobacillus plantarum PL-02 Supplementation Combined With Resistance Training Improved Muscle Mass, Force, and Exercise Performance in Mice

“…Although the mechanisms underlying the relationship between gut microbes and muscle have not been fully defined, researchers have found that exercise training can alter the composition of the gut microbiota, possibly due to energy demand and use ( 13 ). Gut microbes may also stimulate insulin-like growth factor-1 (IGF-1) to increase skeletal muscle mitochondrial levels, promote skeletal muscle cell synthesis ( 14 ), or maintain or improve muscle mass by increasing glycogen storage using short-chain fatty acids (SCFA) ( 15 ). Many factors can cause changes in the gut microbiome, such as diet and exercise.…”