Research Progress of Vitamins on Muscle Regeneration

Su Jing-yan ,Li Ping ,Wen Xin ,Zhang Wen-yu,and Tong Hui-li*

1 Key Laboratory of Animal Cellular and Genetics Engineering of Heilongjiang Province,Northeast Agricultural University,Harbin 150030,China

2 Laboratory of Cell and Developmental Biology,School of Life Sciences,Northeast Agricultural University,Harbin 150030,China

Abstract:Muscle satellite cells,as muscle stem cells,play a critical role in the process of muscle regeneration,and effective muscle regeneration helps to restore muscle function and maintain the homeostasis of muscle tissues.In damaged muscle,muscle satellite cells are activated to form new myofibers through the process of cell proliferation,migration,differentiation and fusion to complete muscle tissue regeneration.Meanwhile,this process is mainly affected by endogenous gene expression and many exogenous factors.Researches in recent years have shown that vitamins,as important nutrients,play an extremely important role in the process of muscle regeneration.Therefore,this article reviewed the roles of vitamins in the regeneration of muscle satellite cells,according to the latest research progress.It would provide more theoretical and data support for the regeneration and repair of muscle damage,muscle atrophy and other muscle diseases,so that it could be better applied in the field of muscle regeneration researches and serve human health.

Key words:vitamin,muscle satellite cell,muscle regeneration

Introduction

Skeletal muscle accounts for 30%-40% of the human body mass and is the largest organ in the human body,undertaking many important biological functions,such as movement,respiration and metabolism of the body.Exercise,trauma,aging,diseases such as muscular dystrophy and other factors can lead to skeletal muscle damage (Saitoet al.,2020;Hiroyukiet al.,2020;Morgan and Partridge,2020).Effective skeletal muscle regeneration helps restore muscle health and maintain muscle tissue homeostasis(Feigeet al.,2018).Therefore,the issue of skeletal muscle regeneration has long been one of the most concerned hot issues in the fields of biology and medicine.It is of great theoretical and practical significance to deeply reveal the mechanism of skeletal muscle regeneration and ensure the healthy physiological and functional state of human muscles.

The regeneration and repair of skeletal muscle after injury mainly depends on skeletal muscle stem cells,among which muscle satellite cells are a type of muscle precursor stem cells with stem cell properties existing in mature skeletal muscle tissues (Relaixet al.,2021).During the embryonic period,muscle satellite cells are activated and proliferate rapidly to form muscle tissues(Schmidtet al.,2019).In adult muscle tissues,they remain in a resting state.When muscles are damaged,exercised,diseased,or stimulated by extracellular signals,muscle satellite cells will show strong regeneration capabilities,which can continuously renew themselves,proliferate,migrate,differentiate and fuse into new muscle cells to ensure the stability of muscle tissues.The differentiation of muscle satellite cells into mature muscle cells is a continuous,programmed,complex and precise biological process,which is an important link in muscle regeneration.

The differentiation of muscle satellite cells is regulated by a series of endogenous genes,mainly by the family of myogenic regulatory factors (MRFs) (Zammit,2017).At the same time,various factors,such as extracellular matrix,cytokines and nutrients,also play a very important role in regulating the regeneration of muscle satellite cells (Saitoet al.,2020;Nguyenet al.,2019).

Studies in recent years have shown that different types of vitamins can improve the activity and regeneration of muscle satellite cells,so they are very important for regulating muscle development and injury regeneration and repair,and solving serious problems that plague human health,such as difficulty in muscle regeneration during muscle atrophy.Its practical application value is worthy of in-depth study.This article reviewed the role of some vitamins in muscle regeneration.

Vitamin D

Vitamin D,with a molecular formula of C28H44O,is a fat-soluble vitamin that plays an important role in maintaining the stability of calcium ions and phosphate in the human body.The effects of vitamin D on muscle development have received extensive attention both in life sciences and clinical researches.In the human body,vitamin D functions in its active form,1,25-dihydroxyvitamin D [1,25(OH)2D].Vitamin D promotes calcium ion absorption and muscle contraction by regulating the activity of ion channels(Ceglia and Harris,2013).In addition,vitamin D regulates the expression of a series of genes by binding to its receptor (Vitamin D receptor,VDR),thereby affecting the growth,development and differentiation of cells.In vitroexperiments showed that vitamin D can promote the proliferation and differentiation of mouse C2C12 myoblasts (van der Meijdenet al.,2016).VDR is widely expressed in muscle cells.Therefore,it can participate in regulating the synthesis of many muscle structural proteins in muscle cells.Activating the expression of VDR can promote muscle hypertrophy and enhance muscle strength (Halfonet al.,2015).In addition,vitamin D inhibits the expression of myostatin (MSTN) in muscle satellite cells by up-regulating the expression of follistatin(FST),and finally promotes the differentiation of muscle satellite cells (Bragaet al.,2017).

In conclusion,vitamin D can promote the regeneration ability of muscle satellite cells by affecting the proliferation and differentiation of muscle satellite cells,and help the recovery of muscle structure and function after muscle injury (Wimalawansa,2019;Iolasconet al.,2021).However,the current clinical researches on the treatment of muscle trauma by supplementing vitamin D is still relatively limited,and more details need to be further explored.

Vitamin A

Vitamin A is a fat-soluble vitamin with a molecular formula of C20H30O.There are two forms of vitamin A1(VA1) and vitamin A2(VA2),both of which have similar physiological functions.Among them,VA1mainly exists in animal liver,blood and retina of the eye,also known as retinol.VA1is an important fatsoluble vitamin that participates in regulating various life activities of the body.VA1produces retinoic acid(RA) through two consecutive oxidation reactions.RA is a metabolic intermediate product of VA1,which is considered to be a signaling molecule involved in neural differentiation,myogenesis and multi-organ development (Liet al.,2017),and participates in various life activities.

Studies have shown that VA1may promote the selfrenewal of embryonic stem cells and germ stem cells through RA (Khillan,2014).Activation of RA signaling promotes myogenic differentiation of C2C12 myoblasts (Zhuet al.,2009).RA promotes myogenic differentiation of muscle stem cells by upregulating c/eBPβexpression and antagonizing TGF-βsignaling pathway (Lamarcheet al.,2015).Zhang(2020) found that VA1promotes the differentiation of mouse C2C12 myoblasts through the pathway of RA formation in dehydrogenase/reductase (SDR) family member 3 (DHRS3).The above studies indicate that vitamin A may regulate muscle differentiation through metabolism into RA,but the direct role of vitamin A in myoblast differentiation and regeneration has not been fully studied and needs further exploration.

Vitamin C

Vitamin C is a polyhydroxy compound with the molecular formula C6H8O6.Vitamin C in nature mainly exists in the form of L-ascorbic acid,and the uptake of vitamin C by cells mainly depends on the sodium-dependent VC transporter (SVCT).The SVCT protein family consists of two active members,SVCT1 and SVCT2 (Liet al.,2022).SVCT2 has a stronger affinity with vitamin C,and SVCT2 is highly expressed in mouse C2C12 and rat L6C5 myoblasts,and is the main transporter of muscle cells for vitamin C uptake (Saviniet al.,2005;Fulzeleet al.,2013).

The role of vitamin C in the regulation of muscle development has received extensive attention (Kimet al.,2013).The addition of vitamin C has a positive effect on the development of leg muscles and the improvement of antioxidant capacity in broilers,and higher VC injections can improve chicken quality(Zhanget al.,2019).Vitamin C plays a certain role in the proliferation,migration and differentiation of young pomfret cells (Duranet al.,2019).In the absence of vitamin C,aged rats have physiological phenomena,such as increased production of reactive oxygen,decreased muscle mass and impaired body functions (Takisawaet al.,2019).

Although VC plays an important regulatory role in muscle development,the molecular mechanism of its role in muscle development remains unclear.The latest research shows that vitamin C can promote the differentiation of mouse C2C12 myoblasts and accelerate the process of muscle injury repair and the formation of new muscle fibers by up-regulating the expression of CSRP3 and promoting the interaction of CSRP3 entering into the nucleus with MyoD and MyoG,respectively (Liet al.,2022).

Vitamin B9

Vitamin B9,also known as folic acid (FA),is a water-soluble B vitamin with a molecular formula of C19H19N7O6.Folic acid is known to play an important role in cellular metabolic activities.Folic acid is necessary for one-carbon metabolism,and it plays a vital role in biochemical processes of cells,such as DNA synthesis,repair,methylation,and biosynthesis of nucleotides and amino acidsin vivo(Tamura and Picciano,2013).Folic acid deficiency will lead to the emergence of many adverse health conditions in the human body,including the occurrence of neurological,cardiovascular and other related diseases.

Cells can uptake folic acid through endocytosis mediated by high-affinity folate receptor proteins (FRα,FR,FRγ) (Zhang,2020).FRαcan promote the proliferation and apoptosis of embryonic cardiomyocytes through the Wnt signaling pathway (Hanet al.,2009).However,in the process of muscle development and regeneration,the expression of FRαand its relationship with folic acid intake are still unclear.

Numerous studies have shown that folic acid plays an important role in the development of embryonic muscle.Supplementing folic acid can promote muscle metabolism and growth (Osteret al.,2017).Hwanget al.(2015) reported that folic acid can induce myogenic differentiation and multinucleated myotube formation of C2C12 cells,and promote the activity of creatine kinase (CK).At the same time,folic acid promotes the differentiation of C2C12 cells through the protein kinase B (PKB) signaling pathway (Liet al.,2018).The latest research showed that myoblasts absorb folic acid through FRα,adding folic acid can promote the translocation of RhoA kinase to the cell membrane,and folic acid promotes the migration of myoblasts through FRαand its downstream RhoA/ROCK signaling pathway.Experiments on muscle injury regeneration in mice have shown that folic acid supplementation can promote the migration and differentiation of muscle satellite cells and accelerate the process of muscle injury repair (Wen,2022).Clarifying the regulatory effect of folic acid on muscle regeneration can provide a basis for the treatment of muscle diseases,such as muscle damage and muscle atrophy,and has broad application prospects

Vitamin B12

Vitamin B12(VB12) is the only vitamin that contains essential minerals,known as red vitamin because of the cobalt.VB12is an indispensable micronutrient for body growth.Animals cannot make VB12by themselves,and the VB12in their bodies comes partly from the synthesis of gastrointestinal microbes and partly from the addition of VB12to food.Therefore,it is important to supplement VB12additives to meet the needs of animals on VB12.The absorption,blood transport and cellular uptake of CNCbl is a complex process involving multiple proteins and receptors (Quadros and Sequeira,2003).CNCbl binds with its transporter TCN2 that binds to its surface receptor CD320 and enters into cells through receptor-mediated endocytosis (En-Nyaet al.,1993).

Yamazakiet al.(1994) described the effects of MeCbl which is an analogue of VB12on the neuromuscular junction and proved that MeCbl promote regeneration of a component of the neuromuscular junction called motor nerve terminal.Although previous reports have confirmed the effects of VB12on neuronal and neuromuscular junctionsin vitroandin vivo,only a few reports confirmed the role of VB12in muscle development.The mechanism by which VB12affects myoblast differentiation is still unclear.

A recent report showed that VB12promotes the differentiation of C2C12 cells and accelerate the process of muscle injury repair by affecting the expression of p-Smad2 in TGF-βsignaling pathway(Liet al.,2022).It will be helpful to explore the application of VB12on skeletal muscle regeneration.

Conclusions

Multivitamins play a regulatory role in muscle development and differentiation,which may promote muscle regeneration by promoting biological processes,such as proliferation,migration,differentiation and fusion of muscle satellite cells.Muscle tissues take different vitamins in different ways,and the action modes of vitamins exerting their activities also vary.In addition,the combined effect of multivitamins may have a better effect on improving muscle regeneration and muscle health.However,due to the limitations of experimental techniques and means,the specific target proteins of different vitamins in muscle cells are still not very clear.Future scientific researches need to accurately screen the target molecules of vitamins and clarify the role of vitamins in promoting the regeneration and differentiation of muscle stem cells,which can provide more theoretical and data support for the regeneration and repair of muscle damage,muscle atrophy and other muscle diseases,so that it can be better applied in the field of muscle regeneration researches and serve human health.