Key Takeaways & Executive Findings
- •• Aging transforms skeletal muscle ECM into a fibrotic barrier through collagen overdeposition, advanced glycation end-product cross-linking, and impaired signaling, creating a vicious cycle of component imbalance, physical stiffening, and functional decline. • The pathological ECM remodeling is a critical driver of muscle aging, not merely a consequence, and represents a key therapeutic target. • A three-tier intervention framework is proposed: restoring ECM homeostasis via exercise, clearing senescent cells to remove upstream drivers, and using tissue engineering for functional reconstruction. • The 'pathological cycle-layered intervention' framework provides a foundation for developing combination therapies and personalized precision medicine for sarcopenia.
Abstract
BACKGROUND: Skeletal muscle aging has been primarily attributed to cellular dysfunction. Emerging evidence indicates that pathological remodeling of the extracellular matrix (ECM) is a core driver. However, a systematic discussion of ECM pathology and intervention strategies is lacking. OBJECTIVE: To systematically elucidate the pathological changes of the ECM in aged skeletal muscle and construct a vicious cycle model of 'component imbalance → physical stiffening → functional decline'. Based on this model, to review multiple potential intervention strategies targeting the ECM. METHODS: A systematic search of PubMed, Web of Science, Scopus, Embase, Cochrane Library, CNKI, Wanfang Data, and VIP was conducted from inception to September 1, 2025. Following predefined inclusion and exclusion criteria, 70 relevant studies were selected from 4,789 articles for comprehensive analysis and review of the pathological mechanisms and interventions for aged skeletal muscle ECM. RESULTS AND CONCLUSION: (1) Aging transforms the ECM from a functional matrix into an inhibitory fibrotic barrier, with core pathology involving three aspects: ① component imbalance: excessive collagen deposition; ② physical stiffening: accumulation of chemical cross-links (e.g., advanced glycation end products); ③ functional decline: impaired ECM signaling that inhibits muscle regeneration. (2) Targeting this pathological cycle, the authors propose a three-tier intervention framework: Tier 1, restoring dynamic balance and physical properties (e.g., exercise); Tier 2, targeting and eliminating upstream drivers (e.g., senescent cells); Tier 3, functional reconstruction using tissue engineering. (3) Pathological ECM remodeling is a key therapeutic target for muscle aging. The proposed 'pathological cycle-layered intervention' framework deepens the understanding of aging mechanisms and provides direction for future combination therapies and personalized precision medicine.
1. Introduction
Skeletal muscle, as a core organ maintaining human motor function and metabolic homeostasis, relies heavily on a precise tissue microenvironment. This microenvironment is composed of muscle fibers, extracellular matrix (ECM), and various stromal cells including muscle stem cells, fibro/adipogenic progenitors, and immune cells, which collectively ensure tissue homeostasis and regenerative potential [1-2]. However, with advancing age, skeletal muscle inevitably undergoes progressive functional decline and structural degeneration, a process known as skeletal muscle aging [3-4].
Traditional views, based on a 'cell-centric' perspective, attribute the root cause of skeletal muscle aging primarily to cellular senescence. This state is characterized by irreversible cell cycle arrest and a secretory phenotype, manifesting as mitochondrial dysfunction and proteostasis imbalance in muscle cells, as well as functional deficits in supporting cells, such as reduced regenerative capacity of muscle stem cells, aberrant adipogenic differentiation of fibro/adipogenic progenitors, and persistent chronic low-grade inflammation [5].
However, accumulating evidence indicates that skeletal muscle aging is not an isolated cellular event; pathological remodeling of the ECM plays a critical role [6]. During aging, the ECM transforms into an inhibitory 'aged matrix' by altering its physical properties and biochemical signals. This aged matrix directly induces and exacerbates functional decline in various cells, creating a vicious cycle that is difficult to reverse [7]. Therefore, this review aims to systematically elaborate the key features, drivers, and molecular mechanisms of ECM remodeling in aged skeletal muscle; deeply analyze the functional impact of the 'aged matrix' on muscle fibers, stem cells, and immune cells, revealing its role in the aging process; and comprehensively review current therapeutic strategies targeting the ECM to improve skeletal muscle function, discussing their challenges and future directions, to provide a theoretical basis and cutting-edge insights for developing novel interventions to delay muscle aging.
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ZHOU Jing, SU Dongming, YANG Dan (2026). Mechanisms and potential therapeutic strategies for skeletal muscle extracellular matrix aging. Chinese Journal of Tissue Engineering Research. https://doi.org/10.12307/2026.21328
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Frequently Asked Questions
What are the main pathological changes in the extracellular matrix during skeletal muscle aging?
The main pathological changes include component imbalance (excessive collagen deposition), physical stiffening (due to accumulation of advanced glycation end products and other cross-links), and functional decline (impaired ECM signaling that inhibits muscle regeneration). These changes transform the ECM from a functional matrix into a fibrotic barrier.
How does the aged extracellular matrix contribute to muscle dysfunction?
The aged ECM becomes stiff and fibrotic, which disrupts mechanotransduction and biochemical signaling. This impairs muscle stem cell function, promotes chronic inflammation, and inhibits muscle regeneration, thereby accelerating muscle weakness and atrophy.
What are the potential therapeutic strategies targeting the extracellular matrix in aging muscle?
Potential strategies include exercise to restore ECM homeostasis, senolytic drugs to clear senescent cells that drive ECM remodeling, and tissue engineering approaches to reconstruct functional ECM. These are organized into a three-tier intervention framework.
Why is the extracellular matrix considered a key therapeutic target for muscle aging?
Because pathological ECM remodeling is not just a consequence but a driver of muscle aging. By targeting the ECM, it may be possible to break the vicious cycle of aging and improve muscle function, offering a more comprehensive approach than targeting cells alone.
What is the 'pathological cycle-layered intervention' framework proposed in this review?
The framework identifies a vicious cycle of ECM component imbalance, physical stiffening, and functional decline. It proposes three intervention layers: (1) restoring dynamic balance and physical properties (e.g., exercise), (2) targeting and eliminating upstream drivers (e.g., senescent cells), and (3) functional reconstruction using tissue engineering. This framework guides combination therapies and personalized medicine.
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