Ageing of skeletal muscle extracellular matrix and mitochondria: finding a potential link

Abstract

Aim: To discuss the progress of extracellular matrix (ECM) characteristics, mitochondrial homeostasis, and their potential crosstalk in the pathogenesis of sarcopenia, a geriatric syndrome characterized by a generalized and progressive reduction in muscle mass, strength, and physical performance.Methods: This review focuses on the anatomy and physiology of skeletal muscle, alterations of ECM and mitochondria during ageing, and the role of the interplay between ECM and mitochondria in the pathogenesis of sarcopenia.Results: Emerging evidence points to a clear interplay between mitochondria and ECM in various tissues and organs. Under the ageing process, the ECM undergoes changes in composition and physical properties that may mediate mitochondrial changes via the systematic metabolism, ROS, SPARC pathway, and AMPK/PGC-1α signalling, which in turn exacerbate muscle degeneration. However, the precise effects of such crosstalk on the pathobiology of ageing, particularly in skeletal muscle, have not yet been fully understood.Conclusion: The changes in skeletal muscle ECM and mitochondria are partially responsible for the worsened muscle function during the ageing process. A deeper understanding of their alterations and interactions in sarcopenic patients can help prevent sarcopenia and improve its prognoses.

Keywords: Ageing; extracellular matrix; mitochondria; reactive oxygen species; sarcopenia.

Figure 1.

The overview of sarcopenia and relevant alterations in mitochondria and ECM. Sarcopenia is a senile syndrome featured by a generalized decline of muscle mass, strength, and physical performance. Mitochondria in skeletal muscle show various age-associated alterations, including mtDNA damage, imbalance of dynamics, biogenesis decline, mitophagy impairment, and ROS overproduction. And the aged ECM exhibits increased collagen deposition and re-organization, leading to a stiffer matrix. ECM: extracellular matrix; mtDNA: mitochondrial DNA; ROS: reactive oxygen species.

Figure 2.

The interplay between mitochondria and ECM during aging. The excessive ROS may contribute to the mechanical tension in stiffer ECM scaffolds through modulating transcription factors, activating RhoA-ROCK pathway, and releasing TGF-β. SPARC can induce ROS generation and activate integrin-linked kinase, contributing to muscle ECM remodelling, altogether differentiating fibroblasts into myofibroblasts, and is further responsible for ECM accumulation in a vicious cycle. ROS: reactive oxygen species; NRF2: nuclear respiratory factor 2; HSF1: heat shock factor 1; ECM: extracellular matrix; α-SMA: α-smooth actin; FAK: focal adhesion kinase; STAT3: FAK-signal transducer and activator of transcription 3; SPARC: secreted protein acidic and rich in cysteine; AMPK: adenosine monophosphate-activated protein kinase; ILK: integrin-linked kinase; TGF-β: transforming growth factor-β.