Aging Disrupts Muscle Stem Cell Function by Impairing Matricellular WISP1 Secretion from Fibro-Adipogenic Progenitors

Abstract

Highlights d Aging alters the myogenic support of FAPs to MuSCs d Aged FAPs produce less matricellular WISP1 d FAP-derived WISP1 is required for MuSC expansion and commitment d Restoring WISP1 levels rejuvenates the myogenic potential of aged MuSCs

Understanding muscle regenerative decline with aging: new approaches to bring back youthfulness to aged stem cells

“…The remaining satellite cells become unresponsive to FGF under regenerative pressure and fail to expand or self‐renew , a defect that is exacerbated by defective fibronectin deposition in old muscles undergoing regeneration, and the consequent impairment in integrin signaling . Aging also impairs the supportive function of fibro‐adipogenic progenitors (FAPs), which fail to induce the matricellular protein Wnt1‐inducible signaling pathway protein 1 (WISP1), required for satellite cell expansion and commitment .…”

“…For example, systemic pharmacological treatments to restore basal autophagy flux preserved quiescence and muscle stem cell regenerative capacity in old muscles . Similarly, systemic delivery of oxytocin restores age‐related regenerative capacity in old muscles , promoting satellite cell activation and proliferation, while systemic delivery of WISP1 during a regenerative event improves myogenic commitment and regenerative success . Moreover, systemic delivery of exogenous α‐Klotho improves muscle stem cell bioenergetics and improves regenerative capacity in aged animals .…”

TGF-β-driven downregulation of the Wnt/β-Catenin transcription factor TCF7L2/TCF4 in PDGFRα+fibroblasts

“…These PDGFRα + MSCs are found in most tissues, including bone marrow, heart, kidney, muscle, nerves, liver, lung, and skin in which they play crucial roles (Carr et al, 2019; Lemos and Duffield, 2018; Lynch and Watt, 2018; Rognoni et al, 2018). Despite their required normal activity during muscle regeneration (Joe et al, 2010; Heredia et al, 2013; Mathew et al, 2011; Fiore et al, 2016; Wosczyna et al, 2019), we and others have reported dysregulated behavior of these precursor cells in models of acute and chronic muscle damage, muscular dystrophy (MD), neurodegenerative diseases, and aging (Acuña et al, 2014; Contreras et al, 2016; Contreras et al, 2019c; González et al, 2017; Kopinke et al, 2017; Madaro et al, 2018; Mahmoudi et al, 2019; Lemos et al, 2015; Lukjanenko et al, 2019; Uezumi et al, 2014a). A common outcome of the dysregulation of these cells is fibrosing disorders, which include non-malignant fibroproliferative diseases with high morbidity and mortality (Lemos and Duffield, 2018; Wynn and Ramalingam, 2012).…”

Regenerating motor neurons prime muscle stem cells for myogenesis by enhancing protein synthesis and mitochondrial bioenergetics

“…The mitogenic activity of different growth factors and cytokines from activated FAPs and macrophages on MuSCs has been well established, and both have been shown to stimulate MuSCs to enter the cell cycle and indelibly change the availability of metabolites in tissue. However, in aging, the cellular and molecular complexion of these cells are altered and contribute to variations in MuSC crosstalk (Lukjanenko et al, 2019).…”