Skeletal muscle fibroblasts in health and disease

Abstract

As the primary producer of extracellular matrix (ECM) proteins in skeletal muscle, fibroblasts play an important role providing structural support to muscle. Skeletal muscle ECM is vital for force transduction from the muscle cells to the tendon and bones to create movement. It is these ECM connections that allow the movement created in muscle to be transmitted to our skeleton. This review discusses how fibroblasts participate in maintaining this healthy ECM within the skeletal muscle. Additionally, from a basic science perspective, we discuss current methods to identify and study skeletal muscle fibroblasts, as this is critical to bettering our understanding of these important cells. Finally, skeletal muscle fibrosis is discussed, which can be a devastating clinical condition characterized by an overproduction of ECM within skeletal muscle. We discuss the role that fibroblasts and other cells play in muscle fibrosis as well as the implications of this work.

The regenerating skeletal muscle niche guides muscle stem cell self-renewal

“…The identity of both fibroblast cohorts was confirmed based on gene enrichment (Supplemental Information Table S1) and on expression of multiple ECM transcripts that include collagen, decorin and fibronectin, whose relative transcript levels were consistently elevated in the postinjury fibroblasts compared to fibroblasts from uninjured muscle (Fig 2E-2F; Supplemental Information Fig S2). Transcripts for gelsolin (Gsn), an actin binding protein, were among few specifically enriched in fibroblasts from uninjured muscle (Supplemental Information Fig S2), while a large number of transcripts were enriched in fibroblasts from injured muscle (5-light blue) including smooth muscle actin (Acta2), periostin (Postn), collagen triple helix repeatcontaining protein 1(cthrc1) and TIMP metallopeptidase inhibitor 1(timp1), all reported to be expressed in activated fibroblasts ( Fig 2G-2H; Supplemental Information Fig S2) (Bagalad, Mohan Kumar, & Puneeth, 2017;Chapman, Meza, & Lieber, 2016;Gladka et al, 2018). Genes expressed in FAPs including CD34, Ly6a (Sca1), and PDGFra do not segregate with a specific cell subpopulation but instead appear dispersed within the entire fibroblast cohort in either uninjured or injured TA muscle ( Fig 2I-2K).…”

“…Remarkable transcriptional changes in the fibroblast, macrophage, and T cell populations occurring by 4 d post injury identify the changes in the cellular environment. For example, smooth muscle actin (Acta2) and periostin (Postn) gene expression increases several hundred fold in fibroblasts indicative of a highly activated state ( Fig 4D), (Baum & Duffy, 2011;Chapman et al, 2016;Gladka et al, 2018;Mann et al, 2011), and is accompanied by a more than 10-fold expression increase in several ECM transcripts that influence MuSC behavior (Collagen 1 (Col1a1), Collagen V (Col5a1), Fibronectin (Fn1) and Biglycan (Bgn) ( Fig 4D) ( Casar, McKechnie, Fallon, Young, & Brandan, 2004;Lukjanenko et al, 2016). Periostin transcription, which increases nearly 400-fold by 4 d post injury is notable because it regulates muscle regeneration and loss of periostin reduces fibrosis in muscular dystrophy (Hara et al, 2018;Latroche et al, 2017;Lorts, Schwanekamp, Baudino, McNally, & Molkentin, 2012) ( Fig 4D).…”

Genetic manipulation of CCN2/CTGF unveils cell‐specific ECM‐remodeling effects in injured skeletal muscle

“…Fibrosis is a process that is largely controlled by resident tissue fibroblast activation and their subsequent expression of collagens and other connective tissue components (5,33). For years, elevated levels of CTGF (or CCN2) have been positively associated with fibrosis, and the role of CTGF in modulating fibroblast activation and their profibrotic phenotype has been well characterized (34).…”

“…Despite the association between CTGF and dystrophic disease progression, the cell-specific contribution of CTGF to dystrophy pathophysiology has not been studied. Fibroblasts are crucial mediators of organ fibrosis (5). When activated, they transformed into collagen-producing myofibroblasts, which are characterized by expression of the marker periostin (24).…”

New Proposal to Define the Fascial System

“…For example, fibroblasts can produce collagen, transform into myofibroblasts and synthesize substances for the ECM. Pericytes are the connective tissue of vessels and are located in the microvascular base membrane, stimulating development and reshaping [17]. Fibroblasts, myofibroblasts, and pericytes produce proteins for the ECM and are located inside it; they have been shown to express α-SMA and vimentin, a stabilizing protein [17,18].…”