Tissue regeneration and gut microbiota-skeletal muscle axis via microRNAs and nutrition: a systematic review

Introduction: In the scenario of muscle regeneration in athletes, maintenance of skeletal muscle function is the prerequisite for tissue homeostasis and increased performance. MicroRNAs play a positive role in expanding our understanding of the controlling factors for skeletal muscle function. Recent progress has been made regarding gut microbiota, regenerative nutrition, and skeletal muscle metabolism. Objective: It was to carry out a systematic review of the main relations of regeneration of skeletal muscle-gut microbiota through nutrological functions, cells, and microRNAs. Methods: The systematic review rules of the PRISMA Platform were followed. The research was carried out from February to April 2023 in Scopus, PubMed, Science Direct, Scielo, and Google Scholar databases. The quality of the studies was based on the GRADE instrument and the risk of bias was analyzed according to the Cochrane instrument. Results and Conclusion: A total of 217 articles were found. A total of 97 articles were fully evaluated and 49 were included and developed in the present systematic review study. Considering the Cochrane tool for risk of bias, the overall assessment resulted in 54 studies at high risk of bias and 34 studies that did not meet the GRADE. It was concluded that miRNAs are widely present in skeletal muscle and play an irreplaceable tuning role in the proliferation, differentiation, apoptosis, development, and other physiological processes of skeletal muscle cells. The proposal that miRNAs are primarily involved in the cell's stress response makes miRNAs ideal for mediating the skeletal muscle response to changes in contractile activity. Research has accumulated evidence that confirms that miRNAs have played an important regulatory role in cell proliferation and differentiation, thus regulating skeletal muscle growth as highlighted in the small intestine by intestinal stem cells (LGR5+). The ketogenic or high-glucose diet regulates the self-renewal balance of LGR5+. Self-renewal and HSC differentiation can be regulated by manipulating vitamin C, A, or D levels and valine restriction. The composition of each athlete's microbiome influences sports performance


Introduction
In the scenario of muscle regeneration in athletes, the maintenance of skeletal muscle function is the prerequisite for tissue homeostasis and increased performance [1,2]. The body needs an effective way to regulate skeletal muscle growth, regeneration, and metabolism to make it in its best state [3][4][5]. In this sense, microRNAs play a positive role in expanding our understanding of the controlling factors for skeletal muscle function and improving the understanding and application of current therapeutic strategies in skeletal muscle diseases [6,7].
Thus, several important findings were informed by studying athletes. Recent progress has been made regarding gut microbiota, regenerative nutrition, and skeletal muscle metabolism [8][9][10]. In this context, regular physical training associated with nutritional health has broad benefits for the health of the gut microbiota [11][12][13].
In this context, physical exercise, nutrition, and gut microbiota are imperative in the process of muscle regeneration. In this context, mesenchymal stem cells (MSC) stand out, such as intestinal stem cells at the base (crypts) of the intestine and muscle stem cells outside the sarcolemma next to the basement membrane of the muscle [14 -16]. The tissue niche is also able to influence MSC metabolism. Tissue stem cell metabolism has focused on central carbon metabolism, ie, the generation of metabolic building blocks via glycolysis, oxidative phosphorylation, or the pentose phosphate pathway. MSCs mediate tissue and organ homeostasis and regeneration by making decisions about whether to remain quiescent, proliferate, or differentiate into mature cell types. These decisions are directly integrated with the body's energy balance and nutritional status [16].
In this sense, along with mesenchymal stem cells, microRNAs have emerged as critical regulators of numerous biological processes, modulating gene expression at the post-transcriptional level. The discovery of microRNAs as important new regulators of gene expression is expected to broaden our biological understanding of the regulatory mechanism in muscle, adding another regulatory dimension to the diversity and complexity of gene regulatory networks. Exerciseinduced skeletal muscle injury and repair have always been at the forefront of sports medicine research. However, many mechanical problems that occur during regeneration and repair after skeletal muscle injury remain unresolved. It has become increasingly clear that regeneration of skeletal muscle development involves regulation by microRNAs. In recent years, the field has seen a rapid expansion of our knowledge of microRNAs in skeletal muscle regeneration. This study reviews microRNAs related to skeletal muscle regeneration and discusses the regulation of their expression in muscle and emerging issues of microRNA regulation [17]. Furthermore, therapeutic approaches point to crucial signaling pathways and molecules responsible for exercise-induced tissue regeneration, such as IGF1, PI3K, and microRNAs [18].
Linked to this, specific GM responses induce the differentiation of a distinct set of RORγ+ regulatory T cells (Treg) crucial for intestinal homeostasis. The highly analogous populations of GM-dependent Treg cells promoted tissue regeneration in extra-intestinal sites, notably severely injured skeletal muscle, and fatty liver. Inflammatory mediators are induced by tissue damage combined with MHC class IIdependent T cell activation to drive the accumulation of gut-derived Treg RORγ+ cells in injured muscle, where they regulate the dynamics and content of early inflammation and help to balance inflammation. proliferation and differentiation of local stem cells [19].
Given the above, the present study aimed to carry out a systematic review of the main relations of skeletal muscle regeneration-gut microbiota through nutrological functions, cells, and microRNAs.

Study Design
The systematic review rules of the PRISMA Platform (Transparent reporting of systematic review and meta-analysis were followed. Available at: www.prismastatement.org/). Accessed on: 05/12/2023.

Data Sources and Research Strategy
The search strategies for this systematic review were based on the keywords (MeSH Terms): "Muscle regeneration. Nutrition. Gut microbiota. microRNAs. Skeletal muscle. Performance. Athletes". The research was carried out from February to April 2023 in Scopus, PubMed, Science Direct, Scielo, and Google Scholar databases. In addition, a combination of keywords with the Booleans "OR", "AND" and the operator "NOT" were used to target scientific articles of interest.

Study Quality and Risk of Bias
The quality of the studies was based on the GRADE instrument and the risk of bias was analyzed according to the Cochrane instrument.

Summary of Literary Findings
A total of 217 articles were found. Initially, duplication of articles was excluded. After this process, the abstracts were evaluated and a new exclusion was performed, removing the articles that did not include the theme of this article, resulting in 151 articles. A total of 97 articles were evaluated in full and 49 were included and developed in this systematic review study ( Figure  1). Considering the Cochrane tool for risk of bias, the overall assessment resulted in 54 studies with a high risk of bias and 34 studies that did not meet GRADE.

Major Findings -Muscle Regeneration and microRNAs
Metabolic homeostasis encompasses the interactions between diet, GM, and cellular enzymatic processes that generate the chemical pathways for perfect physiological and immunological functioning [20][21][22][23][24]. In this context, microRNAs have emerged as important actors in the regulation of gene expression, being involved in most of the biological processes examined so far. The proposal that miRNAs are primarily involved in the cell's stress response makes miRNAs ideal for mediating the skeletal muscle response to changes in contractile activity [25,26].
In this respect, the skeletal muscle fiber, belonging to the terminally undifferentiated cell type, results mainly from the differentiation of myoblasts. Satellite cells in skeletal muscle are a kind of myoblasts in mature skeletal muscle tissue to form new muscle fibers or mix with previous muscle fibers to carry out skeletal muscle growth and development through proliferation and differentiation [27,28].
Thus, muscle-specific miR-1, miR-133, and miR-206 studies have gained great attention in exploring miRNA roles in myogenesis and increasing data from these researches may provide a comprehensive explanation for the mechanisms of myogenesis and the defined signal. cell proliferation and differentiation pathways [29]. Understanding the functions of miR-1 and miR-133 is the first significant step toward understanding the effects of miRNAs on the regulation of skeletal muscle growth and development. miR1's mechanism to promote muscle fiber differentiation may reduce HDAC4 expression and enhance MEF2 activity [32].
Furthermore, miR-206 may also result in increased differentiation of myoblasts [33]. The gap junction protein connexin43 (Cx43) and Pola1 have been confirmed as the regulatory targets of miR-206 [35]. Cx43 must be involved in the initial stage of myogenesis. miR-206 reduces muscle fiber mutual contact by reducing Cx43 expression [35]. Adoption of miR-206 may lead to decreased Pola1 expression, which will reduce DNA synthesis in the early stage of differentiation and restrict cell proliferation during the period of myotube formation [36]. Unlike the functions of miR-1 and miR-206, miR133 can promote myoblast proliferation by suppressing SRF and restricting myoblast differentiation [31,34]. Another muscleenriched miRNA is miR-486, which is highly induced during myoblast differentiation and exerts myogenic function [37].
In addition, when miR-27b expression is contained and PAX3 expression remains at a certain level, cell proliferation will be promoted and differentiation will be delayed. During the transition period from cell proliferation to differentiation, some miRNAs are upregulated while others are down-regulated [38,39].

Gut microbiota, Nutrients and Muscle Performance
The practice of physical activity, endogenous metabolites, and dietary nutrients can directly influence epigenetic enzymes. Epigenetic modifications to DNA and histone proteins alter cell fate by controlling chromatin accessibility and downstream gene expression patterns [18].
Thus, the mechanistic target of the rapamycin complex 1 (mTORC1) can be activated by growth factorinduced signaling only when the amino acids arginine and leucine, as well as the cofactor S-adenosyl methionine (SAM), are detected within the cell. In addition, energy balance communicated via the cellular AMP/ADP-ATP ratio can be detected by AMP-activated protein kinase (AMPK). Furthermore, transcription factors can be directly regulated by metabolites, for example, the kynurenine metabolite of tryptophan is an endogenous aryl hydrocarbon receptor agonist, and alpha-ketoglutarate (α-KG) binds to and activates IKKβ and initiates IKKβ signaling. NF-κβ [21].
In this scenario, dietary manipulations and metabolites may affect tissue stem cell fate decisions, as highlighted in the small intestine (intestinal stem cells (LGR5+)), hematopoietic system (hematopoietic stem cells (HSCs), liver, muscle (muscle stem cells/satellite cells) and hair follicles (hair follicle stem cells (HFSCs).

Vol 16 Iss 2 Year 2023 International Journal of Nutrology
For example, in HFSCs, mitochondrial pyruvate carrier 1 (MPC1) and lactate dehydrogenase (LDHA) regulate the balance between telogen and anagen during the hair cycle. In LGR5+, 3hydroxy-3-methylglutaryl-CoA synthase (Hmgcs2) is highly expressed while MPC1/2 is expressed at low levels. The ketogenic or high-glucose diet regulates the balance of autorenewal of LGR5+ HSC self-renewal and differentiation can be regulated by manipulation of vitamin C, A, or D levels and valine restriction [20].
Concerning muscle regeneration, the nicotinamide riboside-rich diet may increase muscle stem cell numbers and function in a histone deacetylase (SIRT1) dependent manner [40,41]. Muscle stem cells, called satellite cells, are responsible for the maintenance of adult muscle mass and repair after injury. Several studies have demonstrated how changes in innate metabolism interfere with the differentiation of satellite stem cells into mature myocytes. For example, singlecell mapping with histone acetylation has shown that acetylation levels tend to be low in quiescent cells [20,42].
The practice of physical activity, endogenous metabolites, and dietary nutrients can directly influence epigenetic enzymes. Epigenetic modifications to DNA and histone proteins alter cell fate by controlling chromatin accessibility and downstream gene expression patterns [18].
Thus, the mechanistic target of the rapamycin complex 1 (mTORC1) can be activated by growth factorinduced signaling only when the amino acids arginine and leucine, as well as the cofactor S-adenosyl methionine (SAM), are detected within the cell. In addition, energy balance communicated via the cellular AMP/ADP-ATP ratio can be detected by AMP-activated protein kinase (AMPK). Furthermore, transcription factors can be directly regulated by metabolites, for example, the kynurenine metabolite of tryptophan is an endogenous aryl hydrocarbon receptor agonist, and alpha-ketoglutarate (α-KG) binds to and activates IKKβ and initiates IKKβ signaling. NF-κβ [21].
In this scenario, dietary manipulations and metabolites may affect tissue stem cell fate decisions, as highlighted in the small intestine (intestinal stem cells (LGR5+)), hematopoietic system (hematopoietic stem cells (HSCs), liver, muscle (muscle stem cells/satellite cells) and hair follicles (hair follicle stem cells (HFSCs). For example, in HFSCs, mitochondrial pyruvate carrier 1 (MPC1) and lactate dehydrogenase (LDHA) regulate the balance between telogen and anagen during the hair cycle. In LGR5+, 3hydroxy-3-methylglutaryl-CoA synthase (Hmgcs2) is highly expressed while MPC1/2 is expressed at low levels. The ketogenic or high-glucose diet regulates the balance of autorenewal of LGR5+ HSC self-renewal and differentiation can be regulated by manipulation of vitamin C, A, or D levels and valine restriction [20].
Concerning muscle regeneration, the nicotinamide riboside-rich diet may increase muscle stem cell numbers and function in a histone deacetylase (SIRT1) dependent manner [40,41]. Muscle stem cells, called satellite cells, are responsible for the maintenance of adult muscle mass and repair after injury. Several studies have demonstrated how changes in innate metabolism interfere with the differentiation of satellite stem cells into mature myocytes. For example, singlecell mapping with histone acetylation has shown that acetylation levels tend to be low in quiescent cells [20,42].

Conclusion
It was concluded that miRNAs are widely present in skeletal muscle and play an irreplaceable tuning role in the proliferation, differentiation, apoptosis, development, and other physiological processes of skeletal muscle cells. The proposal that miRNAs are primarily involved in the cell's stress response makes miRNAs ideal for mediating the skeletal muscle response to changes in contractile activity. Research has accumulated evidence that confirms that miRNAs have played an important regulatory role in cell proliferation and differentiation, thus regulating skeletal muscle growth as highlighted in the small intestine by intestinal stem cells (LGR5+). The ketogenic or high-glucose diet regulates the self-renewal balance of LGR5+. Selfrenewal and HSC differentiation can be regulated by manipulating vitamin C, A, or D levels and valine restriction. The composition of each athlete's microbiome influences sports performance.