Xiang-Yu Deng,Shao-Hua Zhou,Cheng-Han Zhou,Li-Feng Meng*

1Department of Nephrology,The First Affiliated Hospital,Guangxi University of Traditional Chinese Medicine,Nanning 530023,China.

Abstract Uremia,as a serious disease endangering human life and health,is often accompanied by many complications,and sarcopenia is one of the most common complications in uremic patients.In recent years,with the increase of the prevalence of uremic sarcopenia,the quality of life of patients has been greatly affected,increasing the mortality of patients.Therefore,how to prevent and treat uremic sarcopenia has become the main research direction to improve the quality of life of patients and reduce mortality.Modern medicine believes that mitochondria play a leading role in the occurrence and development of uremic sarcopenia.At the same time,the author found that uremic sarcopenia was closely related to the spleen of traditional Chinese medicine through reading ancient medical literature,and spleen dysfunction,spleen disease and kidney were the key factors for uremic sarcopenia.This article will analyze and summarize the pathogenesis and research of the disease from the perspective of traditional Chinese and western medicine,so as to provide basis for clinical prevention and treatment of uremic sarcopenia.

Keywords:spleen;mitochondrion;uremic sarcopenia;overview

Background

Due to the differences in diagnostic methods,measurement methods,and ethnic groups,the prevalence of uremic sarcopenia worldwide is about 4%–63%[1–3].Although the occurrence of sarcopenia is mainly related to aging,it can also be observed under different pathological conditions unrelated to aging,and the complication of sarcopenia is particularly obvious in late chronic kidney disease(CKD)[4].With the gradual failure of renal function of patients,the degree of sarcopenia also increases,and sarcopenia is closely related to the quality of life and mortality of uremic patients[5].In recent years,modern and traditional Chinese medicine have conducted a lot of research on the disease,each with its special advantages in treating it.Therefore,this article will review the pathogenesis and treatment of the disease from modern and traditional Chinese medicine.

Understanding of uremic sarcopenia

sarcopenia,also known as sarcopenia,is a syndrome characterized by a progressive and systemic decline in muscle mass and strength[6].At the same time,uremic sarcopenia is a kind of muscular dystrophy related to CKD,which is caused by mitochondrial dysfunction and low inflammation state of uremic patients to accelerate muscle consumption[7].In recent years,with the development of dialysis technology,the survival time of uremic patients has been extended,but the complications of uremic sarcopenia are more and more common.

Modern medical research on uremic sarcopenia

Pathogenesis of uremic sarcopenia

Up to now,the pathogenesis of uremic sarcopenia has not been fully understood.Still,it is generally believed that uremic sarcopenia is mainly related to metabolic acidosis,chronic inflammatory state,vitamin D deficiency,IR,hormone change,intestinal ecological imbalance,and other complications of uremic patients,and the occurrence of these complications is closely related to mitochondrial disorder[8].In patients with end-stage renal disease(ESRD),muscle mitochondria’s content and oxidation capacity decreased,and the activities of various mitochondrial enzymes were inhibited,leading to energy production damage[9].At the cellular level,changes in the mitochondrial population are often considered to be a key factor in the complex etiology of sarcopenia[10].Mitochondrial dysfunction will lead to the production of reactive oxygen species and promote the accumulation of uremic toxins and the aggravation of chronic inflammation[11].These toxins and inflammation can change the balance of cell protein by increasing protein degradation and reducing protein synthesis,promoting muscle protein consumption,and leading to a decline in muscle quality and strength[10,12].In view of the fact that dialysis treatment is the most mainstream treatment method for uremic patients at present,this treatment method will further aggravate the degradation and reduction of protein synthesis of patients,thus leading to the decline of muscle quality and strength of patients[13].The decreased exercise volume caused by the reduction of skeletal muscle will promote low inflammatory reaction and mitochondrial damage.The continuous low inflammatory state and damaged mitochondria will further increase uremic toxin,thus damaging renal function[14].Therefore,sarcopenia and uremia form a positive feedback loop of a vicious circle.

Prevention and treatment of uremic sarcopenia

As there is no specific drug approved for the treatment of uremic sarcopenia at present,and drug intervention lacks proven efficacy,exercise therapy and nutrition therapy are the strongest treatment interventions for sarcopenia in the population of ESRD[15,16].

Nutritional therapy

Nutritional therapy is a part of medical treatment,including oral nutritional supplements,amino acid supplements,parenteral nutrition during dialysis,enteral nutrition and other nutritional supplements,to maintain or restore the best nutritional status and health,so as to delay the occurrence of sarcopenia in uremic patients.Mariana Ayala et al.through the clinical trial of 109 elderly hemodialysis patients who were given oral nutritional supplements for 3 months during dialysis,it was found that oral nutritional supplements could improve the protein energy consumption and nutritional status of dialysis patients,thereby easing the process of muscle loss[17].Since the kidneys of uremic patients are basically unable to excrete protein and other metabolic wastes,leading to the accumulation of a large number of uremic toxins in the body,multidisciplinary teams are required to assess the risk of uremic sarcopenia and determine the optimal protein intake of each patient[18].Research shows that a high-quality protein diet combined with essential amino acids can help maintain the good nutritional status of patients with advanced renal disease and prevent patients from wasting[19].The enteral administration of nutrients can nourish the gastrointestinal mucosa,improve its integrity,and not be damaged by uremic toxins.Due to the high requirements of total parenteral nutrition,parenteral administration of nutrients must be selected only in the case of severe gastrointestinal dysfunction(such as intestinal ischemia,gastrointestinal obstruction,or peritonitis)[20].According to various studies,fiber,as a special nutritional supplement,can reduce the urotoxin produced by intestinal microbiota,and reduce the creatinine and azotemia values,thus delaying the development of sarcopenia in patients[21].

Exercise therapy

ESRD patients often lack physical activity in daily life,which aggravates chronic inflammation and loss of muscle mass and strength[22].At present,it has been proved that physical exercise can gradually increase muscle mass and muscle strength,reduce the degree of muscle loss,and is the most effective way to alleviate sarcopenia.Studies have shown that exercise can significantly improve the volume of quadriceps femoris in CKD patients under conservative treatment [23].A multicenter retrospective observational study,“the relationship between six-month resistance training and muscle strength or physical performance in maintenance hemodialysis patients”,made 306 patients receive a six-month resistance exercise plan three times a week during hemodialysis.The research results showed that resistance training could significantly improve the muscle strength of maintenance hemodialysis(MHD)patients[24].Zhi-Juan Dong et al.passed 41 MHD patients with sarcopenia were divided into the control group(21 cases),which only received routine hemodialysis care and the intervention group(21 cases)who received high or medium-intensity resistance exercise in dialysis three times a week for 12 weeks based on routine hemodialysis care[25].The experimental results showed that medium and high-intensity resistance exercise in dialysis could improve the muscle condition and dialysis effect of MHD patients with sarcopenia.Similarly,the randomized controlled experiment on the influence of resistance training before dialysis on the characteristics of muscle loss and inflammation in patients with chronic kidney disease shows that 24 weeks of resistance training before dialysis can also improve the status of muscle loss and inflammation[26].

Traditional Chinese medicine(TCM)research on uremic myopenia

TCM pathogenesis of uremic sarcopenia

In the theory of traditional Chinese medicine,uremia can be categorized as Guange,Longbi,Edema,etc.[27].The name“Guange”was first formally proposed in Zhong-Jing Zhang’s“Treatise on Cold Damage Diseases(3rd Century)”,which generally refers to the disease of dysuria and vomiting[28].The TCM classic“Criterion of Syndrome and Treatment(Ken-Tang Wang,1368–1644 C.E.)”says:“the spleen is the Yin(The negative side of something or movement,such as inner,downward,restrained,heavy,qualitative,etc.)organ,and the spleen disease is full of Yin,which is the internal pass”.This article clearly points out that the disease of Guange is related to the deficiency of spleen Yang(The outward,upward,exuberant,light,and functional aspects of things and movements.).The spleen and kidney are Yang deficient,and the Qi(In traditional Chinese medicine,it refers to themost fundamental and subtle substances that constitute the human body and maintain life activities.At the same time,it also has the meaning of physiological function.In terms of traditional Chinese medicine,Qi and different words are used together to express different meanings.)is not good.The damp poison is excessive inside,which can block up and transform into heat.The internal attack is upwardly opposed,and the kidney can not be closed,which is called“Guange”[29].Currently,there is no corresponding TCM name for sarcopenia in the TCM literature.Still,some scholars judged it to be similar to the“flaccidity syndrome”with clinical manifestations of muscle wasting,flaccidity and weakness,and slow movement in TCM according to the symptoms,such as decreased quality and strength of the disease[30].“Suwen·Weilun”in the Warring States Period:“the spleen governs the muscles of the body,which clearly states that the muscle is dominated by the spleen and fully describes the relationship between the spleen and the muscle[31].In the basic theory of traditional Chinese medicine,the spleen belongs to the five zang viscera(The heart,liver,spleen,lungs and kidneys are collectively known as the five organs,which have the function of transformation and storage,and are physiologically characterized by hiding essence without diarrhea and being full but not solid.The five organs in TCM are not limited to anatomical concepts.).It is the root of the acquired.“The spleen is responsible for the transportation of water and grain and the production of muscle,so it is responsible for the meat”,which is from“Suwen Annotation Collection”by Zhi-Cong Zhang in the Ming and Qing Dynasties.It is pointed out from the physiological point of view that the muscle establishes its relationship through the water and grain essence moistened by the spleen.“If your spleen heat(dampness and heat in the middle Jiao,obstructing the Qi of the spleen,resulting in pathological changes of dysfunctional transportation and elevation.),your stomach will be dry and thirsty,and your muscles will be unkind,which will lead to flaccidity”.It comes from the“Suwen·Weilun”.It pointed out that because the spleen has heat evil and burns the body fluid,the muscle becomes insensitive due to dystrophy and finally becomes flaccid.The ancient medical book“Suwen Bi Lun Pian”in the Warring States Period:“muscle arthralgia is endless,feeling evil again,and giving up in the spleen”.It is believed that if the muscle is insensitive for a long time and feels the invasion of exogenous pathogens,the spleen will be damaged,showing that the spleen and sarcopenia are closely related and mutually affected.“Spleen and Stomach Theory”by Dong-Yuan Li of the Yuan Dynasty:“spleen deficiency leads to lean muscles”,pointing out that spleen deficiency leads to lean muscles,which explains the close relationship between spleen and sarcopenia from the pathological aspect.The spleen is the source of Qi and blood biochemistry.If the spleen is deficient,it can not regenerate Qi and blood,and the muscles lose nourishment,which leads to muscle weakness.Over time,it will develop into sarcopenia.

To sum up,it can be seen that the pathogenesis of uremia is spleen and kidney Yang deficiency.The kidney governs the Yin and Yang of the human body.The kidney Yin and kidney Yang are the roots of the Yin and Yang of the five zang viscera and six fu viscera(The gallbladder,stomach,large intestine,small intestine,Sanjiao and bladder are collectively called the six organs,which have the functions of receiving,transferring and excreting,and are physiologically characterized by transferring and transforming things without hiding them,and real but not full.).If the kidney Yang deficiency can not warm and nourish the spleen Yang,it causes the spleen Yang deficiency,and the spleen Yang deficiency can lead to the dystrophy of the body’s muscles.Therefore,it can be seen that the spleen is closely related to uremic sarcopenia.The“Inner Canon of the Yellow Emperor(221 B.C.E.–220 C.E.)”says,“the spleen governs muscles,and the spleen governs the abdomen”.Uremic patients need a long period of peritoneal dialysis treatment.Peritoneal dialysis can induce peritoneal fibrosis in patients,leading to impairment of the function of spleen governing the large abdomen and temper damage,which will aggravate the skeletal muscle reduction syndrome of uremic patients.Therefore,the TCM pathogenesis of uremic sarcopenia is spleen Qi deficiency so that we can treat uremic sarcopenia from the direction of“spleen”in TCM.

TCM treatment of uremic myopenia

At present,it is widely believed that the spleen governing muscle in traditional Chinese medicine is closely related to mitochondrial metabolism in modern medicine.The method of invigorating the spleen and replenishing Qi can improve the quality of skeletal muscle by changing the function of mitochondria[32].The spleen is the acquired root,which can promote human growth and development,and is the primary basis for maintaining human physiology and life activities.Mitochondria,as a bilayer membrane organelle existing in most cells,are not only a critical cell structure for producing the energy needed by the human body but also can regulate apoptosis of human cells.Mitochondrial dysfunction will lead to sarcopenia[33].Therefore,it can be concluded that there are many similarities between the physiological function of the spleen in traditional Chinese medicine and the mitochondria in cells,and a correlation between“spleen mitochondria”can be established[34].The spleen dysfunction leads to a change in mitochondrial functional mechanism,which leads to skeletal muscle failure.Therefore,the method of invigorating the spleen and replenishing Qi is the main idea of TCM in treating uremic myopenia[35].

Treatment of uremic myopenia with traditional Chinese medicine

Wei Li found that Sijunzi decoction,a spleen-invigorating and Qi enriching drug,can further inhibit skeletal muscle aging by increasing the activities of superoxide dismutase,glutathione peroxidase and other antioxidant enzymes in serum and rectus femoris[36].Yu-Juan Wu et al.for uremic patients undergoing peritoneal dialysis,the prescription for invigorating the spleen and replenishing Qi(based on Sijunzi decoction,get rid of ginseng participate inAstragali Radix,

Codonopsis Radix,Salviae Miltiorrhizae Radix et Rhizoma,Chuanxiong Rhizoma,Puerariae Radix,andArecae Pericarpium)was applied[37].It was found that the prescription for invigorating the spleen and replenishing Qi could improve the nutritional status of patients,thereby relieving skeletal muscle loss.Tian-Yang Cheng et al.found through the animal experiment on autophagy of skeletal muscle of chronic renal failure rats by Jianpi Yiqi Xiaoyu Xiezhuo formula that Jianpi Yiqi Xiaoyu Xiezhuo formula can not only enhance and improve the renal function of rats but also alleviate the reduction of muscle quality and strength by curbing autophagy of skeletal muscle[38].According to the TCM theory of“spleen governing muscle”,the therapeutic principle of uremic sarcopenia is to strengthen the spleen and replenish Qi in both experiment and clinic.

Monomer of traditional Chinese medicine for uremic myopenia

The study found that the monomer of traditional Chinese medicine can also play a role in preventing and treating uremic myopenia.Ginsenoside Rb1 rich in ginseng can improve the energy metabolism of skeletal muscle in rats and delay muscle aging[39].Astragalus membranaceus is sweet in nature.It can restore the spleen and the lung meridians.It is an essential medicine for tonifying Qi and blood.Modern research has found that astragaloside A in astragalus membranaceus protects the kidney and has the effects of anti-inflammation and anti-oxidation,increasing the body’s immunity and skeletal muscle contraction[40].Angelica sinensis,known as the medicine of blood in Qi,contains angelica polysaccharide,which has the effect of anti-inflammation and promoting the enlargement of muscle tubes to achieve the purpose of delaying skeletal muscle atrophy[41,42].Epimedium,which has the effects of tonifying kidney Yang and strengthening muscles and bones,can improve rat muscle’s antioxidant capacity and free radical scavenging capacity and delay muscle atrophy[43].

Acupuncture and moxibustion treatment of uremic myopenia

The“Suwen·Weilun”in the Warring States Period says,“those who treat impotence should only take advantage of masculinity”.Bi-Yuan Liu et al.applied the acupuncture treatment principle of“taking Yang Ming alone for flaccidity”and used acupuncture at Zusanli(ST36),Sanyinjiao(SP6)and Taixi(KI3)point to treat patients with sarcopenia and achieved good clinical efficacy[44].ST36 belongs to the foot Yangming meridian and has the function of strengthening the spleen and stomach.As the intersection point of the three Yin meridians of spleen,liver,kidney,and foot,SP6 can strengthen thespleen and kidney.As the original point of foot Shaoyin meridian,KI3 can nourish kidney Yin.The coordination of the three points can replenish the spleen and kidney and alleviate the process of muscle atrophy.Chun-Chun Yuan et al.found in animal experiments that acupuncture at Dazhui point and Shenshu(BL23),Pishu(BL20),ST36,and other points on both sides of rats can improve the quality of skeletal muscle in rats[45].Similarly,taking Shousanli(LI10),ST36,BL20,and BL23 from rats can improve myasthenia gravis[46].

Massage treatment of uremic myopenia

Massage is a physical therapy of external treatment of traditional Chinese medicine.It refers to the massage of acupoints and the gentle stimulation of the meridians,acupoints,and joint muscles with the help of strength,to achieve the function of dredging the meridians,activating Qi,and activating blood circulation.Massage can improve the strength of skeletal muscle.Jing Yang found that it can replenish the spleen and kidney,promote blood circulation and smooth channels,and improve patients’muscle quality and strength through clinical observation on the manipulation of Yangming meridians in patients with muscle deficiency[47].Yong-Jun Zhao et al.found through the clinical experiment of the influence of massage combined with resistance exercise on patients with skeletal muscle attenuation that massage combined with resistance exercise can effectively improve the skeletal muscle quality,muscle strength,walking ability and overall activity ability of patients with skeletal muscle attenuation than the simple resistance exercise[48].

Summary and outlook

To sum up,this paper discusses the pathogenesis of uremic sarcopenia from the perspective of modern medicine and traditional Chinese medicine,expounds on the relationship between spleen governing muscle and mitochondrial metabolism,and discusses the methods of modern medicine and traditional Chinese medicine to prevent and treat uremic sarcopenia.According to the basic theory of traditional Chinese medicine,“the spleen governs the limbs,and the spleen governs the movement”.It can promote the prevention and treatment of uremic myopenia with exercise and nutrition therapy in modern medicine.To a certain extent,it is similar to the treatment of invigorating spleen and Qi in traditional Chinese medicine.However,at present,we have not yet clarified traditional Chinese medicine’s molecular biological mechanism in treating uremic sarcopenia.In the future,we should continue to combine the TCM theory of uremic sarcopenia with modern medical technology.To study the mechanism of strengthening spleen and replenishing Qi to improve mitochondrial metabolism and treat uremic myopenia at the molecular biological level.To better prevent the occurrence and development of uremic myopenia,improve the quality of life of patients,and reduce the mortality of patients.