A glitch in the matrix: the pivotal role for extracellular matrix remodeling during muscle hypertrophy

Abstract

Multinuclear muscle fibers are the most voluminous cells in skeletal muscle and the primary drivers of growth in response to loading. Outside the muscle fiber, however, is a diversity of mononuclear cell types that reside in the extracellular matrix (ECM). These muscle-resident cells are exercise-responsive and produce the scaffolding for successful myofbrillar growth. Without proper remodeling and maintenance of this ECM scaffolding, the ability to mount an appropriate response to resistance training in adult muscle is severely hindered. Complex cellular choreography takes place in muscle following a loading stimulus. These interactions have been recently revealed by single-cell explorations into muscle adaptation with loading. The intricate ballet of ECM remodeling involves collagen production from fibrogenic cells and ECM modifying signals initiated by satellite cells, immune cells, and the muscle fibers themselves. The acellular collagen-rich ECM is also a mechanical signal-transducer and rich repository of growth factors that may directly influence muscle fiber hypertrophy once liberated. Collectively, high levels of collagen expression, deposition, and turnover characterizes a well-trained muscle phenotype. The purpose of this review is to highlight the most recent evidence for how the ECM and its cellular components affect loading-induced muscle hypertrophy. We also address how the muscle fiber may directly take part in ECM remodeling, and whether ECM dynamics are rate-limiting for muscle fiber growth.

Multi-transcriptome analysis following an acute skeletal muscle growth stimulus yields tools for discerning global and MYC regulatory networks

“…Interstitial cells of the muscle microenvironment are generally viewed as the primary contributors to ECM deposition and turnover. Emerging evidence suggests that muscle fibers also play a major role in ECM remodeling (53,(56)(57)(58), which the current data reinforces.…”

Resistance and endurance exercise training improves muscle mass and the inflammatory/fibrotic transcriptome in a rhabdomyosarcoma model

“…Although RET had no effect on muscle fibrosis, which was similar to our previous work with endurance exercise following radiation exposure, 15 genes involved in PDGF and Hedgehog signalling, two pro‐fibrotic pathways, 37,38 were down‐regulated in the RMS + Tx‐RET compared to RMS + Tx‐SED, suggesting RET as a potential exercise intervention to decrease the fibrogenic potential of FAPs. Hypertrophic stimuli induce ECM remodelling by stimulating pathways involved in ECM degradation and synthesis, which facilitates ECM reorganization and promotes myofibre growth 39 . Our transcriptomic data indicate that ECM reorganization is ongoing in RET facilitated by diverse matrix metalloproteinases ( Mmp14 , Mmp3 , Mmp2 , etc.)…”

“…Hypertrophic stimuli induce ECM remodelling by stimulating pathways involved in ECM degradation and synthesis, which facilitates ECM reorganization and promotes myofibre growth. 39 Our transcriptomic data indicate that ECM reorganization is ongoing in RET facilitated by diverse matrix metalloproteinases ( Mmp14 , Mmp3 , Mmp2 , etc.) and with collagen biosynthesis and modification and collagen degradation pathways both enriched in RMS + Tx‐RET versus RMS + Tx‐SED.…”

Role of Matrix Metalloproteinases in Musculoskeletal Diseases

“…MD types include the common conditions related to joints (arthritis, rheumatoid arthritis, osteoarthritis (OA), psoriatic arthritis, and gout); bones (osteoporosis, traumatic fractures, and osteopenia); muscles (sarcopenia); other parts of the body (neck and back pain, fibromyalgia, vasculitis) [ 3 ] and genetic disorders such as achondroplasia, muscular dystrophy, and osteogenesis imperfecta [ 4 ]. Matrix metalloproteinases (MMPs) play a crucial role in maintaining the structural integrity of ECM [ 5 ]. Pathophysiological events in musculoskeletal diseases promote ECM remodeling and MMPs expression [ 1 , 6 ].…”