Encyclopedia
Please note this is a comparison between Version 1 by Akihito Tsubota and Version 2 by Rita Xu.
The liver plays a pivotal role in nutrient/energy metabolism and storage, anabolic hormone regulation, ammonia detoxification, and cytokine production. Impaired liver function can cause malnutrition, hyperammonemia, and chronic inflammation, leading to an imbalance between muscle protein synthesis and proteolysis. Patients with chronic liver disease (CLD) have a high prevalence of sarcopenia, characterized by progressive loss of muscle mass and function, affecting health-related quality of life and prognosis. Recent reports have revealed that osteosarcopenia, defined as the concomitant occurrence of sarcopenia and osteoporosis, is also highly prevalent in patients with CLD. Since the differentiation and growth of muscles and bones are closely interrelated through mechanical and biochemical communication, sarcopenia and osteoporosis often progress concurrently and affect each other. Osteosarcopenia further exacerbates unfavorable health outcomes, such as vertebral fracture and frailty. Therefore, a comprehensive assessment of sarcopenia, osteoporosis, and osteosarcopenia, and an understanding of the pathogenic mechanisms involving the liver, bones, and muscles, are important for prevention and treatment. This review summarizes the molecular mechanisms of sarcopenia and osteosarcopenia elucidated to data in hopes of promoting advances in treating these musculoskeletal disorders in patients with CLD.
- chronic liver disease
- sarcopenia
- osteoporosis
- osteosarcopenia
1. Introduction
Sarcopenia is a syndrome characterized by decreased muscle mass and function (strength and/or physical performance) [1][2][3][4][5][1,2,3,4,5]. In 1989, Rosenberg proposed the concept of sarcopenia as the age-related loss of muscle mass [6]. Later research emphasized that loss of muscle function is important for diagnosing sarcopenia, which can occur regardless of age [1][2][3][4][5][1,2,3,4,5]. The European Working Group on Sarcopenia in Older People (EWGSOP) has classified sarcopenia into primary (when no other cause exists other than aging) and secondary (when the condition is caused by underlying diseases such as chronic liver disease (CLD)) [1]. The liver is a multifunctional organ involved in glucose and energy metabolism, hormonal regulation, cytokine production, and ammonia detoxification. Impairment of liver function can cause malnutrition, hyperammonemia, chronic inflammation, and imbalance of muscle protein synthesis and proteolysis, leading to sarcopenia [5][7][5,7]. Thus, sarcopenia is highly prevalent in patients with CLD, especially those with liver cirrhosis (LC) (30–70%) [8]. Notably, sarcopenia negatively affects health-related quality of life and prognosis, and increases the risk of complications, such as infection [9][10][9,10].
Several studies revealed a close relationship between sarcopenia and osteoporosis in community-dwelling older adults. This finding has fueled the concept of osteosarcopenia, defined as the concomitant occurrence of sarcopenia and osteoporosis [11][12][13][14][11,12,13,14]. These two musculoskeletal disorders affect each other and share a common genetic, mechanical, and biochemical pathophysiology [15][16][17][18][15,16,17,18]. Osteosarcopenia has been associated with more negative health outcomes than either sarcopenia or osteoporosis alone, increasing the risk of falls, fractures, and mortality [19]. Therefore, it has been described as a “hazardous duet” [19]. Our recent studies revealed that osteosarcopenia frequently develops and is associated with fractures, low physical performance, and frailty in patients with CLD [20][21][22][20,21,22]. Although sarcopenia and osteosarcopenia are a global health concern, appropriate assessment and early diagnosis of these musculoskeletal disorders in patients with CLD remain inadequate in real-world clinical settings. Furthermore, treatment strategies for osteosarcopenia in CLD have yet to be established, limiting our understanding of the pathogenic mechanisms involving the liver, bones, and muscles in patients with CLD.
2. Osteosarcopenia in Chronic Liver Disease
2.1. Prevalence and Clinical Significance of Osteosarcopenia in Patients with Chronic Liver Disease
In 2009, Binkley and Buehring advocated the concept of sarco-osteoporosis, which was then defined as the concomitant occurrence of sarcopenia and osteoporosis and has now evolved into the term “osteosarcopenia” [14]. Patients with osteosarcopenia have an increased risk of falls and fractures, resulting in a poor quality of life and increased mortality [23][24][81,82]. The prevalence of osteosarcopenia in community-dwelling older adults is 8.4 %, 12.7%, and 19.2 % in Japan, China, and Korea, respectively [11][12][13][11,12,13]. In a Korean study of patients aged ≥60 years with hip fractures, the prevalence of osteosarcopenia was 28.7%, and the 1-year mortality of osteosarcopenia (15.1%) was higher than that of the normal (7.8%), osteoporosis-alone (5.1%), and sarcopenia-alone (10.3%) groups [25][83]. Furthermore, patients with osteosarcopenia had higher scores for disability, frailty, and depression than those without it [13]. A recent pooled analysis of the aging general population demonstrated that osteosarcopenia increases the risk of fractures [odds ratio (OR), 2.46], falls (OR, 1.62), and mortality (OR, 1.66) [26][84].
As shown in Table 12, several studies have investigated the prevalence and clinical significance of osteosarcopenia in patients with CLD [20][21][22][27][28][20,21,22,85,86]. In one study of 142 patients with LC, the proportion of patients in the normal, sarcopenia-alone, osteoporosis-alone, and osteosarcopenia groups was 53.5%, 12.0%, 12.7%, and 21.8%, respectively [20]. In the osteosarcopenia group, the values of the skeletal muscle mass index (SMI) and handgrip strength were the lowest, whereas the prevalence of vertebral fractures was the highest (61.3%) among all four groups [20]. In another study of 117 patients with primary biliary cholangitis (PBC), the prevalence of osteosarcopenia was 15.4% [21]. Patients with osteosarcopenia had a higher prevalence of vertebral fractures than those without osteoporosis and sarcopenia (55.6% vs. 6.7%) [21]. In the other study of 291 patients with CLD, 49 (16.8%) and 81 (27.8%) had osteosarcopenia and frailty, respectively [22]. Frailty and vertebral fractures more frequently occurred in patients with osteosarcopenia than in those without (79.6% vs. 17.4% and 59.2% vs. 20.2%, respectively) [22]. Patients with osteosarcopenia also showed a greater impairment of physical performance and balance than those without osteosarcopenia, resulting in an increased risk of falls and fractures [29][87]. Furthermore, vertebral and hip fractures can cause impaired physical function and immobility, thereby leading to sarcopenia [30][31][88,89]. These findings suggest that osteosarcopenia and fractures are closely interrelated and exacerbate the negative health outcomes of each other.
Table 12.
Representative previous studies on osteosarcopenia in patients with chronic liver disease.
| Authors (Year, Country) [Reference] |
Patients Characteristics | Prevalence of Osteosarcopenia | Diagnostic Method for Osteosarcopenia (Criteria for Sarcopenia) |
Main Findings | |
|---|---|---|---|---|---|
| Hayashi et al. (2018, Japan) [27] | Hayashi et al. (2018, Japan) [85] |
112 patients with CLD (LC, 36.0%) |
7.1% | DEXA and BIA (JSH) | Sarcopenia and LC were significantly associated with the BMD. Sarcopenia (OR, 6.16) and LC (OR, 15.8) were independent risk factors for osteoporosis. |
| Bering et al. (2018, Brazil) [28] | Bering et al. (2018, Brazil) [86] |
104 patients with CHC | ― | DEXA (EWGSOP) | Low BMD, low muscle strength, pre-sarcopenia, and sarcopenia were noticed in 34.6%, 27.9%, 14.4%, and 8.7% of subjects, respectively. Appendicular skeletal muscle mass was an independent predictor of BMD. Sarcopenia was independently related to bone mineral content. |
| Saeki et al. (2020, Japan) [21] |
117 patients with PBC (LC, 9.4%) |
15.4% | DEXA and BIA (JSH) | The SMI and handgrip strength were significantly correlated with the BMD. Patients with osteosarcopenia had a higher prevalence of vertebral fracture (55.6%) than those without both sarcopenia and osteoporosis (6.7%). | |
| Saeki et al. (2020, Japan) [22] |
291 patients with CLD (LC, 51.9%) |
LC 20.5% Non-LC 12.9% |
DEXA and BIA (JSH) | Frailty was an independent risk factor associated with osteosarcopenia (OR, 9.837), and vice versa (OR, 10.069). The prevalence of frailty and vertebral fracture was significantly higher in patients with osteosarcopenia than in those without osteosarcopenia (79.6% vs. 17.4% and 59.2% vs. 20.2%, respectively). |
Abbreviations: BIA, bioelectrical impedance analysis; BMD, bone mineral density; CHC, chronic hepatitis C; CLD, chronic liver disease; DEXA, dual-energy X-ray absorptiometry; EWGSOP, European Working Group on Sarcopenia in Older People; JSH, Japan Society of Hepatology; LC, liver cirrhosis; OR, odds ratio; PBC, primary biliary cholangitis; SMI, skeletal muscle mass index.
2.2. Pathogenic Mechanisms of Osteosarcopenia: Relationship between Muscle and Bone
Given that muscles and bones are closely related during their development and growth, it is conceivable that sarcopenia, osteoporosis, and osteosarcopenia often progress in conjunction with each other [15][16][17][18][15,16,17,18]. Therefore, an understanding of the relationship between muscles and bones along with the underlying pathogenesis of osteosarcopenia is essential from a therapeutic point of view. Although the pathogenesis of osteosarcopenia in CLD is not fully elucidated, we addressed the possible mechanisms herein.
2.2.1. Mechanical Factors
Increasing the mechanical load on the skeletal muscles leads to protein synthesis and muscle hypertrophy, while the opposite causes muscle atrophy [32][90]. The maintenance of bone mass and strength depends on the contribution of the following skeletal muscle-derived mechanical forces: (1) the tensile forces generated by contracting muscles at their insertion site; (2) the compressive forces between bones generated by muscles contracting through joints; and (3) the bending forces that long bones receive when the muscles generate the force to lift the object held distally [32][90]. The expression level of IGF-1, which has a positive effect on muscles and bones, is increased by exercise-induced mechanical loading [17]. Accordingly, reduced physical activity cannot maintain skeletal muscle and bone mass, resulting in the development and progression of sarcopenia and osteoporosis.
2.2.2. Genetic Factors
During embryogenesis, muscles and bones originate from a common mesenchymal precursor, and their development is controlled by common genes and growth factors [33][91]. Therefore, genetic factors may influence both sarcopenia and osteoporosis. A genome-wide association study (GWAS) of Han Chinese and US Caucasians revealed that three single nucleotide polymorphisms in or near the glycine-N-acyltransferase (GLYAT) gene, which is essential for the regulation of glucose and energy metabolism, were associated with bone size and muscle mass [34][92]. A subsequent GWAS in the US identified METTL21C as a pleiotropic gene for bones and muscles [35][93]. METTL21C is highly expressed in muscles and plays an important role in myoblastic differentiation, calcium homeostasis, and survival of osteocytes against apoptosis through the modulation of NF-κB signaling [17][35][17,93]. In addition, myocyte enhancer factor 2C (MEF-2C) and α-actinin 3 (ACTN3) are candidate genes with a pleotropic effect on bones and muscles [36][94]. MEF-2C is a transcriptional regulatory protein involved in skeletal muscle development, sarcomeric gene expression, and fiber-type control; loss of MEF-2C results in disorganized myofibers [37][95]. MEF-2C also regulates bone homeostasis by modulating osteoclastic bone resorption, and deletion of MEF-2C results in increased bone mass [38][96]. ACTN3 is highly expressed in fast glycolytic muscle fibers and contributes to the differentiation of muscle fibers toward the fast-twitch type [39][97]. Additionally, ACTN3 is expressed in osteoblasts, and the deletion of ACTN3 reduces bone mass [40][98].
2.2.3. Chronic Inflammation
The production of reactive oxygen species (ROS) and proinflammatory cytokines, such as IL-1β, IL-6, and TNF-α, is increased in chronic disease conditions, including CLD [41][42][99,100]. Chronic inflammation inhibits protein synthesis and osteoblast differentiation and promotes protein breakdown and osteoclastic bone resorption, which lead to skeletal muscle and bone mass loss [5][17][5,17]. Advanced glycation end products (AGEs), which are induced by non-enzymatic glycation, oxidation, and chronic inflammation, suppress the expression of myogenic genes and impair the osteoblasts’ function, thereby affecting the quality of bone produced [17][43][17,101]. Pentosidine is one of the major AGEs and its well-characterized cross-link has been studied in bone tissues. The levels of pentosidine increases with age, and high levels of pentosidine are a risk factor for fractures in older adults. Serum pentosidine levels were reported to be negatively correlated with skeletal muscle mass in postmenopausal women with diabetes [44][102]. Notably, plasma pentosidine levels were increased in patients with a decreased liver functional reserve as well as in those with prevalent fractures [45][103]. Similar to other pathological conditions, CLD (especially LC) also facilitates a reduction in both skeletal muscle mass and bone mass and quality.
2.2.4. Myokines
Skeletal muscle cells secrete various endocrine molecules, such as IGF-1, myostatin, irisin, beta-aminoisobutyric acid (BAIBA), fibroblast growth factor 2 (FGF2), IL-6, IL-7, IL-15, and osteoglycin, which influence bone metabolism [15][16][17][18][15,16,17,18]. IGF-1 is synthesized primarily in the liver and is also produced by muscles and bones [17]. As described above, IGF-1 regulates skeletal muscle protein synthesis via the PI3K/AKT/mTOR pathway. Moreover, IGF-1 stimulates osteoblast proliferation and contributes to the maintenance of bone mass and strength [46][47][104,105]. When CLD progresses to the advanced stages, serum IGF-1 levels decrease, leading to a loss of skeletal muscle and bone mass [48][47][44,105]. As described above, myostatin acts as a negative regulator of muscle cell proliferation and protein synthesis and is inhibited by IGF-1 and testosterone. Serum myostatin levels have not only been revealed to be higher in patients with decompensated LC than in those with compensated LC and healthy controls, but have also been associated with muscle mass loss and worse survival [49][50][106,107]. Notably, myostatin also negatively regulates bone formation and metabolism by promoting osteoclast differentiation [51][108]. Inhibition of the myostatin pathway results in an increase in not only muscle mass but also bone mass [52][109]. Irisin, a hormone-like myokine produced by skeletal muscles in response to physical exercise, is released into the circulation by cleavage of the fibronectin type Ⅲ domain-containing protein 5 (FNDC5) and plays a crucial role in the regulation of bone metabolism [53][54][110,111]. Administration of recombinant irisin increases cortical bone mass and strength and promotes pro-osteoblastic genes and osteoblastic bone formation, and it also reduces the effect of osteoblast inhibitors [55][112]. Intriguingly, irisin is highly expressed in hepatocytes, Kupffer cells, and sinusoidal endothelial cells in the human liver [56][113]. This suggests that CLD may decrease irisin levels that may subsequently affect bone mass and strength. Among patients with LC, it was revealed that not only were the serum irisin levels lower in sarcopenic patients than in non-sarcopenic patients, but also associated with sarcopenia [54][111]. FNDC5 deficiency impairs autophagy and fatty acid oxidation and enhances lipogenesis in the liver via the AMPK/mTOR pathway [57][114]. BAIBA, a small molecule secreted by skeletal muscles during exercise, protects osteocytes against ROS-induced apoptosis and prevents bone loss [58][115].
2.2.5. Osteokines
As bones secrete various substances that affect other organs, they may also be considered as endocrine organs. Bones secrete various osteokines such as osteocalcin, sclerostin, Wnt, TGF-β, fibroblast growth factor 23 (FGF23), and prostaglandin E2 (PGE2), which affect the metabolism of not only bones but also muscles [15][16][17][18][15,16,17,18]. Osteocalcin is a noncollagenous protein secreted from osteoblasts [59][116]. Osteocalcin-deficient (Ocn−/−) mice showed reduced muscle mass, and treatment with exogenous osteocalcin increased muscle mass in older mice, whereas deletion of osteocalcin resulted in increased bone mass [60][61][117,118]. In contrast, another study using newly generated Ocn−/− mice demonstrated that osteocalcin was not involved in the regulation of bone quantity and muscle mass [62][119]. Therefore, the impact of osteocalcin on muscles and bones remains controversial. The Wnt/β-catenin signaling pathway promotes osteoblast differentiation and osteogenesis and is involved in prenatal myogenesis and skeletal muscle regeneration/fibrosis [63][64][120,121]. Sclerostin, a protein encoded by the Sost gene and produced by mature osteocytes, acts as a negative regulator of the Wnt/β-catenin pathway, and therefore inhibits bone formation [65][122]. In patients with PBC, sclerostin was found to be expressed in the bile duct epithelium and was associated with the severity of cholangitis. In addition, the serum sclerostin levels in patients with PBC were higher than those in controls, suggesting its potential involvement in impaired bone formation [66][123]. A Korean study of healthy non-diabetic subjects showed that serum sclerostin levels were negatively correlated with skeletal muscle mass [67][124]. However, sclerostin-deficient mice showed greater trabecular bone volume and lower muscle mass than did wild-type mice [68][125]. Therefore, further studies are needed to clarify the role of sclerostin in the muscle–bone relationship. TGF-β, which is produced by osteoblasts and involved in the regulation of bone remodeling and homeostasis [69][126], induces muscle fiber atrophy by upregulating the E3 ubiquitin ligase atrogin-1 in mice [70][127]. In a mouse model of osteolytic bone metastases, bone-derived TGF-β contributed to muscle weakness by decreasing Ca2+-induced muscle force production [71][128].
2.2.6. Vitamin D
The liver plays a crucial role in vitamin D metabolism. When the liver’s function is impaired, bone and muscle homeostases are dysregulated through vitamin D metabolism [72][73][129,130]. Vitamin D is not only involved in the intestinal absorption of calcium and phosphate and maintenance of appropriate circulating concentrations of these minerals, but also contributes to normal bone mineralization [72][73][129,130]. Vitamin D deficiency causes secondary hyperparathyroidism, leading to an increased bone turnover and consequent bone loss. An in vitro study of C2C12 skeletal muscle cells reported that vitamin D promoted the differentiation of myogenic cells by increasing the expression and nuclear translocation of the vitamin D receptor (VDR) and modulating promyogenic and antimyogenic factors [74][131]. VDR knockout and vitamin D-deficient mice showed decreased muscle mass and strength, dysregulation of myogenic regulatory factors, and increased myostatin and MuRF1 [75][132]. Reportedly, the rate of patients with CLD who frequently exhibited vitamin D deficiency (≤20 ng/mL) ranged from 47% to 87% [76][133]. In one study of patients with CLD, serum vitamin D levels were positively correlated with skeletal muscle mass and handgrip strength, and low vitamin D levels were associated with sarcopenia [77][134]. Our study revealed that low vitamin D levels, especially severe vitamin D deficiency (≤10.5 ng/mL), were closely related to sarcopenia and frailty in patients with CLD [76][133]. These findings suggest that maintaining sufficient levels of vitamin D is important for preventing loss of skeletal muscle and bone mass.
