a-cross-sectional-study-association-serum-uric-acid-levels-sarcopenia

A Cross-Sectional Study of the Association of Serum Uric Acid Levels and Sarcopenia using the China Health and Retirement Longitudinal Study (CHARLS)

Previous research has yielded inconsistent findings concerning the relationship between serum uric acid (UA) levels and sarcopenia. However, there is ...

single-port-non-liposuction-endoscopic-axillary-lymph-node-dissection

Single-port Non-liposuction Endoscopic Axillary Lymph Node Dissection in Breast Cancer Surgery

Breast cancer is the most common malignant tumor among women worldwide. For patients with a high axillary lymph node burden, axillary lymph node ...

The First Affiliated Hospital of Chongqing Medical University

The Sixth Affiliated Hospital of Sun Yat-sen University

Sun Yat-sen University

Obesity is associated with biological dysfunction in skeletal muscle. As a condition of obesity accompanied by muscle mass loss and physical dysfunction, sarcopenic obesity (SO) has become a novel public health problem. Human fibroblast growth factor 19 (FGF19) plays a therapeutic role in metabolic diseases. However, the protective effects of FGF19 on skeletal muscle in obesity and SO are still not completely understood. Our results showed that FGF19 administration improved muscle loss and grip strength in young and aged mice fed a high-fat diet (HFD). Increases in muscle atrophy markers (FOXO-3, Atrogin-1, MuRF-1) were abrogated by FGF19 in palmitic acid (PA)-treated C2C12 myotubes and in the skeletal muscle of HFD-fed mice. FGF19 not only reduced HFD-induced body weight gain, excessive lipid accumulation and hyperlipidaemia but also promoted energy expenditure (PGC-1α, UCP-1, PPAR-γ) in brown adipose tissue (BAT). FGF19 treatment restored PA- and HFD-induced hyperglycaemia, impaired glucose tolerance and insulin resistance (IRS-1, GLUT-4) and mitigated the PA- and HFD-induced decrease in FNDC-5/irisin expression. However, these beneficial effects of FGF19 on skeletal muscle were abolished by inhibiting AMPK, SIRT-1 and PGC-1α expression. Taken together, this study suggests that FGF19 protects skeletal muscle against obesity-induced muscle atrophy, metabolic derangement and abnormal irisin secretion partially through the AMPK/SIRT-1/PGC-α signalling pathway, which might be a potential therapeutic target for obesity and SO.

FGF19 protects skeletal muscle against obesity-induced muscle atrophy, metabolic derangement and abnormal irisin levels via the AMPK/SIRT-1/PGC-α pathway.

Age-related loss of skeletal muscle mass and function, termed sarcopenia, could impair the quality of life in the elderly. The mechanisms involved in skeletal muscle aging are intricate and largely unknown. However, more and more evidence demonstrated that mitochondrial dysfunction and apoptosis also play an important role in skeletal muscle aging. Recent studies have shown that mitochondrial calcium uniporter (MCU)-mediated mitochondrial calcium affects skeletal muscle mass and function by affecting mitochondrial function. During aging, we observed downregulated expression of mitochondrial calcium uptake family member3 (MICU3) in skeletal muscle, a regulator of MCU, which resulted in a significant reduction in mitochondrial calcium uptake. However, the role of MICU3 in skeletal muscle aging remains poorly understood. Therefore, we investigated the effect of MICU3 on the skeletal muscle of aged mice and senescent C2C12 cells induced by D-gal. Downregulation of MICU3 was associated with decreased myogenesis but increased oxidative stress and apoptosis. Reconstitution of MICU3 enhanced antioxidants, prevented the accumulation of mitochondrial ROS, decreased apoptosis, and increased myogenesis. These findings indicate that MICU3 might promote mitochondrial Ca homeostasis and function, attenuate oxidative stress and apoptosis, and restore skeletal muscle mass and function. Therefore, MICU3 may be a potential therapeutic target in skeletal muscle aging.

MICU3 regulates mitochondrial Ca-dependent antioxidant response in skeletal muscle aging.

Aging-related sarcopenia is currently the most common sarcopenia. The main manifestations are skeletal muscle atrophy, replacement of muscle fibers with fat and fibrous tissue. Excessive fibrosis can impair muscle regeneration and function. Lysyl oxidase-like 2 (LOXL2) has previously been reported to be involved in the development of various tissue fibrosis. Here, we investigated the effects of LOXL2 inhibitor on D-galactose (D-gal)-induced skeletal muscle fibroblast cells and mice. Our molecular and physiological studies show that treatment with LOXL2 inhibitor can alleviate senescence, fibrosis, and increased production of reactive oxygen species in fibroblasts caused by D-gal. These effects are related to the inhibition of the TGF-β1/p38 MAPK pathway. Furthermore, in vivo, mice treatment with LOXL2 inhibitor reduced D-gal-induced skeletal muscle fibrosis, partially enhanced skeletal muscle mass and strength and reduced redox balance disorder. Taken together, these data indicate the possibility of using LOXL2 inhibitors to prevent aging-related sarcopenia, especially with significant fibrosis.

Lysyl oxidase-like 2 inhibitor rescues D-galactose-induced skeletal muscle fibrosis.

Sarcopenia seriously affects the quality of life of the elderly, but its molecular mechanism is still unclear. Degeneration in muscle innervation is related to age-related movement disorders and muscle atrophy. The expression of CHRNA1 is increased in the skeletal muscle of the elderly, and in aging rodents. Therefore, we investigated whether CHRNA1 induces the occurrence and development of sarcopenia. Compared with the control group, local injection of AAV9-CHRNA1 into the hindlimb muscles decreased the percentage of muscle innervation. At the same time, the skeletal muscle mass decreased, as manifested by a decrease in the gastrocnemius mass index and the cross-sectional area of the muscle fibers. The function of skeletal muscle also decreased, which was manifested by decreases of compound muscle action potential and muscle contractility. Therefore, we concluded that upregulation of CHRNA1 can induce and aggravate sarcopenia.

CHRNA1 induces sarcopenia through neuromuscular synaptic elimination.

While the exact mechanism remains unclear, type 2 diabetes mellitus increases the risk of sarcopenia which is characterized by decreased muscle mass, strength, and function. Whole-transcriptome RNA sequencing and informatics were performed on the diabetes-induced sarcopenia model of db/db mice. To determine the specific function of lncRNA Gm20743, the detection of Mito-Sox, reactive oxygen species, Ethynyl-2'-deoxyuridine, and myosin heavy chain was performed in overexpressed and knockdown-Gm20743 C2C12 cells. RNA-seq data and informatics revealed the key lncRNA-mRNA interactions and indicated a potential regulatory role of lncRNAs. We characterized three core candidate lncRNAs Gm20743, Gm35438, 1700047G03Rik, and their potential function. Furthermore, the results suggested lncRNA Gm20743 may be involved in regulating mitochondrial function, oxidative stress, cell proliferation, and myotube differentiation in skeletal muscle cells. These findings significantly improve our understanding of lncRNAs that may mediate muscle mass, strength, and function in diabetes and represent potential therapeutic targets for diabetes-induced sarcopenia.

The Whole-transcriptome Landscape of Diabetes-related Sarcopenia Reveals the Specific Function of Novel lncRNA Gm20743.

Primary sarcopenia is a multicausal skeletal muscle disease associated with muscle strength and mass loss. Skeletal muscle fibrosis is one of the significant pathological manifestations associated with the development of age-related sarcopenia. Irisin, which is cleaved by the extracellular domain of fibronectin type Ⅲ domain-containing protein 5 (FNDC5), has previously been reported to exert antifibrotic effects on the heart, liver, and pancreas, but whether it can rescue skeletal muscle fibrosis remains unknown. In this study, we examined the effects of irisin on D-galactose (D-gal)-induced skeletal muscle fibroblasts. We found that D-gal-induced senescence, fibrosis, and redox imbalance were inhibited by irisin treatment. Mechanistically, irisin or FNDC5 overexpression attenuated D-gal-induced senescence, redox imbalance, and fibrosis by regulating the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) signaling pathway. Overall, irisin might be a promising therapeutic candidate for age-related skeletal muscle fibrosis.

Irisin ameliorates D-galactose-induced skeletal muscle fibrosis via the PI3K/Akt pathway.

Muscle atrophy and skeletal muscle fibrosis are significant pathological manifestations of primary sarcopenia. The regulation of C2C12 myoblast and skeletal muscle fibroblast apoptosis is associated with these pathological changes. Previous studies have indicated that irisin, the cleaved form of fibronectin type III domain-containing protein 5 (FNDC5), can alleviate primary sarcopenia. However, the mechanisms of the effect of irisin in age-related apoptosis remain unknown. Our present research aimed to explore the effect of irisin and the underlying mechanism of D-galactose (D-gal)-induced apoptosis in skeletal muscle fibroblasts and C2C12 myoblasts. We found the opposite effects of D-gal on C2C12 myoblasts and fibroblasts. We also found that irisin suppressed C2C12 cell apoptosis and promoted fibroblast apoptosis. Mechanistically, irisin altered D-gal-induced apoptosis by increasing caveolin-1 expression. Taken together, these findings further demonstrated that irisin is a potential agent that can treat aged-relative muscle atrophy and fibrosis.

Irisin alters D-galactose-induced apoptosis by increasing caveolin-1 expression in C2C12 myoblasts and skeletal muscle fibroblasts.

Chronic hyperglycemia can damage the microcirculation, which impairs the function of various organs and tissues and predisposes individuals to chronic complications. Sarcopenia (SP) is the age-related decline in muscle mass and function that contributes to the sequelae of type 2 diabetes. In particular, diabetic patients are at higher risk of SP because of insulin resistance, chronic inflammation, and decreased physical activity.

Sarcopenia-associated factors and their bone mineral density levels in middle-aged and elderly male type 2 diabetes patients.

To investigate the effects of Astragalus polysaccharide (APS) on skeletal muscle structure and function in D-galactose (D-gal)-induced C57BL/6J mice.

Effects of Astragalus polysaccharide on the structure and function of skeletal muscle in D-galactose-induced C57BL/6J mice.

Ferroptosis has been implicated in skeletal muscle aging. Nevertheless, specific ferroptosis-related genes (FRGs) governing skeletal muscle aging remain unclear. The aim of this study was to identify ferroptosis-related marker genes associated with skeletal muscle aging, uncovering potential therapeutic targets for skeletal muscle aging. Data from GSE38718 was utilized to identify differentially expressed FRGs (DE-FRGs) in aging versus normal human skeletal muscle by the least absolute shrinkage and selection operator (LASSO) and the support vector machine recursive feature elimination (SVM-RFE) algorithms. Validation was conducted using RT-qPCR and Western blot in aging mouse muscle and D-galactose (D-gal)-treated C2C12 cells. SLC38A1 was identified as a significantly downregulated marker for aging skeletal muscle. Overexpression of SLC38A1 mitigated cellular aging in D-gal treated C2C12 cells. In both D-gal treated and sh-SLC38A1 C2C12 cells, increased ROS levels, elevated mtROS, higher intracellular iron concentrations, and intensified lipid peroxidation were observed. In contrast, SLC38A1 overexpression markedly reduced the accumulation of ROS, mtROS, iron concentration, and lipid peroxidation associated with D-gal treatment in these cells. In conclusion, through screening analyses and validation experiments, we identified SLC38A1 as a ferroptosis-related regulator for skeletal muscle aging.

SLC38A1 protects against aging-related oxidative stress and lipid peroxidation in C2C12 myoblasts: Implication of a ferroptosis-related regulator for skeletal muscle aging.

ArticleTotal : 2	Year
Publication title	2025
Publication title	2026

Article	Year
FGF19 protects skeletal muscle against obesity-induced muscle atrophy, metabolic derangement and abnormal irisin levels via the AMPK/SIRT-1/PGC-α pathway. Journal of cellular and molecular medicine\| PubMed ID: 33751819	2021
MICU3 regulates mitochondrial Ca-dependent antioxidant response in skeletal muscle aging. Cell death & disease\| PubMed ID: 34845191	2021
Lysyl oxidase-like 2 inhibitor rescues D-galactose-induced skeletal muscle fibrosis. Aging cell\| PubMed ID: 35712918	2022
CHRNA1 induces sarcopenia through neuromuscular synaptic elimination. Experimental gerontology\| PubMed ID: 35809807	2022
The Whole-transcriptome Landscape of Diabetes-related Sarcopenia Reveals the Specific Function of Novel lncRNA Gm20743. Communications biology\| PubMed ID: 35915136	2022
Irisin ameliorates D-galactose-induced skeletal muscle fibrosis via the PI3K/Akt pathway. European journal of pharmacology\| PubMed ID: 36539073	2023
Irisin alters D-galactose-induced apoptosis by increasing caveolin-1 expression in C2C12 myoblasts and skeletal muscle fibroblasts. Molecular and cellular biochemistry\| PubMed ID: 38581552	2025
Sarcopenia-associated factors and their bone mineral density levels in middle-aged and elderly male type 2 diabetes patients. World journal of diabetes\| PubMed ID: 39676813	2024
Effects of Astragalus polysaccharide on the structure and function of skeletal muscle in D-galactose-induced C57BL/6J mice. American journal of translational research\| PubMed ID: 39822540	2024
SLC38A1 protects against aging-related oxidative stress and lipid peroxidation in C2C12 myoblasts: Implication of a ferroptosis-related regulator for skeletal muscle aging. Experimental gerontology\| PubMed ID: 40907901	2025

Yongxin Wu

Biography

JoVE Journal Publications

Other Publications