Fecal transplant from myostatin deletion pigs positively impacts the gut-muscle axis
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Curated by eLife
eLife assessment
Myostatin KO is known to increase muscle mass, but can transplanting the gut microbiome from these animals also increase muscle mass and strength? Based on the experiments performed in this paper, the answer is yes, and the positive impact of myostatin deletion on the gut-muscle axis may proceed through alteration of gut bacterial metabolism, including short-chain fatty acids. This is important work and will contribute to the expanding field of the gut-muscle axis.
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Abstract
The host genome may influence the composition of the intestinal microbiota, and the intestinal microbiota has a significant effect on muscle growth and development. In this study, we found that the deletion of the myostatin ( MSTN ) gene positively regulates the expression of the intestinal tight junction-related genes TJP1 and OCLN through the myosin light-chain kinase/myosin light chain pathway. The intestinal structure of MSTN −/− pigs differed from wild-type, including by the presence of a thicker muscularis and longer plicae. Together, these changes affect the structure of intestinal microbiota. Mice transplanted with the intestinal microbiota of MSTN −/− pigs had myofibers with larger cross-sectional areas and higher fast-twitch glycolytic muscle mass. Microbes responsible for the production of short-chain fatty acids (SCFAs) were enriched in both the MSTN −/− pigs and recipient mice, and SCFAs levels were elevated in the colon contents. We also demonstrated that valeric acid stimulates type IIb myofiber growth by activating the Akt/mTOR pathway via G protein-coupled receptor 43 and ameliorates dexamethasone-induced muscle atrophy. This is the first study to identify the MSTN gene-gut microbiota-SCFA axis and its regulatory role in fast-twitch glycolytic muscle growth.
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eLife assessment
Myostatin KO is known to increase muscle mass, but can transplanting the gut microbiome from these animals also increase muscle mass and strength? Based on the experiments performed in this paper, the answer is yes, and the positive impact of myostatin deletion on the gut-muscle axis may proceed through alteration of gut bacterial metabolism, including short-chain fatty acids. This is important work and will contribute to the expanding field of the gut-muscle axis.
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Reviewer #1 (Public Review):
In this study, Luo, Han, and Yin et al. conduct a fecal microbiota transplant from MSTN KO pigs exhibiting hypertrophy to recipient antibiotic-depleted B6 mice. The microbiota transplants successfully transferred muscle hypertrophy phenotypes to the mice. Aspects of the pig gut microbiome were recapitulated in the recipient mice, including a higher abundance of Romboutsia and valeric acid. The authors then demonstrate that 5 weeks of daily gavage of valerate, but not isobutyrate or water, was sufficient to increase type IIb myofiber growth and GA muscle mass, and protect mice against dexamethasone-induced muscle atrophy. Taken together, these data neatly demonstrate that genetic disruption of the myostatin gene results in a microbiome-dependent increase in valeric acid, which in turn results in significantly …
Reviewer #1 (Public Review):
In this study, Luo, Han, and Yin et al. conduct a fecal microbiota transplant from MSTN KO pigs exhibiting hypertrophy to recipient antibiotic-depleted B6 mice. The microbiota transplants successfully transferred muscle hypertrophy phenotypes to the mice. Aspects of the pig gut microbiome were recapitulated in the recipient mice, including a higher abundance of Romboutsia and valeric acid. The authors then demonstrate that 5 weeks of daily gavage of valerate, but not isobutyrate or water, was sufficient to increase type IIb myofiber growth and GA muscle mass, and protect mice against dexamethasone-induced muscle atrophy. Taken together, these data neatly demonstrate that genetic disruption of the myostatin gene results in a microbiome-dependent increase in valeric acid, which in turn results in significantly altered skeletal muscle growth.
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Reviewer #2 (Public Review):
I would like to congratulate the authors for testing the hypothesis that the gut microbiome from animals that lack myostatin is sufficient to improve muscle-related measures (except treadmill running time). Subsequent experiments should examine if the identified bacteria are sufficient, on their own, to impact muscle, which may open the field to muscle-improving probiotics. Alternatively, data for the SCFA, valerate, may foster approaches aimed at improving muscle with SCFA supplementation. RCTs are needed to test these hypotheses.
Strengths include a translational approach, including findings in pigs, in colonized mice, and in cells.
Weaknesses include the need to normalize muscle-related measures to body weight. Is muscle mass increased, for example, when divided by body weight? If not it would argue …
Reviewer #2 (Public Review):
I would like to congratulate the authors for testing the hypothesis that the gut microbiome from animals that lack myostatin is sufficient to improve muscle-related measures (except treadmill running time). Subsequent experiments should examine if the identified bacteria are sufficient, on their own, to impact muscle, which may open the field to muscle-improving probiotics. Alternatively, data for the SCFA, valerate, may foster approaches aimed at improving muscle with SCFA supplementation. RCTs are needed to test these hypotheses.
Strengths include a translational approach, including findings in pigs, in colonized mice, and in cells.
Weaknesses include the need to normalize muscle-related measures to body weight. Is muscle mass increased, for example, when divided by body weight? If not it would argue against the role of fecal transplantation in increasing muscle mass from myostatin KO pigs.
The authors achieved their aims, and the results support their conclusions.
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Reviewer #3 (Public Review):
The link between gut microbiota and maintenance of skeletal muscle mass was demonstrated in previous publications (including Lahiri et al., 2019), which also revealed that supplementing germ-free mice with a cocktail of short-chain fatty acids (SCFAs) could rescue the decreased skeletal muscle mass of germ-free mice. Increased MSTN expression in skeletal muscle causes sarcopenia (Cho et al., 2022). Moreover, the idea that Myostatin (MSTN) changes the composition of intestinal microorganisms is not novel (Pei et al., 2021 and Wen et al., 2022). In this manuscript, Quan et al. showed that knockout of MSTN in pigs affected the composition of gut microbes and that fecal microbiota transplantation (FMT) from MSTN KO pigs into mice caused hypertrophy of the GP muscle via activation of the Akt/mTOR pathway and …
Reviewer #3 (Public Review):
The link between gut microbiota and maintenance of skeletal muscle mass was demonstrated in previous publications (including Lahiri et al., 2019), which also revealed that supplementing germ-free mice with a cocktail of short-chain fatty acids (SCFAs) could rescue the decreased skeletal muscle mass of germ-free mice. Increased MSTN expression in skeletal muscle causes sarcopenia (Cho et al., 2022). Moreover, the idea that Myostatin (MSTN) changes the composition of intestinal microorganisms is not novel (Pei et al., 2021 and Wen et al., 2022). In this manuscript, Quan et al. showed that knockout of MSTN in pigs affected the composition of gut microbes and that fecal microbiota transplantation (FMT) from MSTN KO pigs into mice caused hypertrophy of the GP muscle via activation of the Akt/mTOR pathway and increased presence of fast type IIb fibers. This effect was attributed to MSTN KO FMT-derived valeric acid, a SCFA, which when administered alone could recapitulate the phenotype of mice that were subjected to MSTN KO FMT. While the phenotypic results of this study are convincing, it lacks novelty in that the mechanisms that are studied were previously known. Instead, it would be interesting to explore how exactly does MSTN affect the composition of gut microbiota. This question was only briefly addressed (the authors showed that MSTN KO leads to changes in intestinal structure), however, a causal relationship was not established. Also, it is unclear how the mechanism of action of valeric acid is any different from the cocktail of acetic acid, butyric acid, or propanoic acid that was previously used. Therefore, overall, this study scores lowly in uniqueness. Nevertheless, the link of gut microbiota to MSTN is interesting and should be pursued by the authors in greater detail.
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