Adult stem cells at work: regenerating skeletal muscle

Abstract

Skeletal muscle regeneration is a finely tuned process involving the activation of various cellular and molecular processes. Satellite cells, the stem cells of skeletal muscle, are indispensable for skeletal muscle regeneration. Their functionality is critically modulated by intrinsic signaling pathways as well as by interactions with the stem cell niche. Here, we discuss the properties of satellite cells, including heterogeneity regarding gene expression and/or their phenotypic traits and the contribution of satellite cells to skeletal muscle regeneration. We also summarize the process of regeneration with a specific emphasis on signaling pathways, cytoskeletal rearrangements, the importance of miRNAs, and the contribution of non-satellite cells such as immune cells, fibro-adipogenic progenitor cells, and PW1-positive/Pax7-negative interstitial cells.

Keywords: Heterogeneity; Myogenesis; Regeneration; Satellite cell; Skeletal muscle; Stem cell.

Fig. 1

Myogenic lineage progression and expression profile of key myogenic regulators. a Schematic illustration of the myogenic lineage progression. Satellite cells are activated, e.g., due to injury, start to proliferate, thereby generating myogenic progenitor cells. Upon differentiation, myogenic progenitor cells differentiate into myocytes, which fuse to form myotubes and mature to become myofibers, the contractile unit of skeletal muscle. b Expression profile of key modulators of myogenic lineage progression

Fig. 2

Regeneration of skeletal muscle. Time course of changes in cellular composition during skeletal muscle regeneration following cardiotoxin (CTX) injury. Satellite cells (in green) are quiescent in resting skeletal muscle. Five days after CTX injury, regenerating muscles are reduced to mostly mono-nuclear cells (satellite cells, immune cells, etc.), but are able to form new myotubes at day 7, which mature to multinucleated myofibers. Of note, the nuclei of intact myofibers are located at the periphery, while newly regenerating myofibers are characterized by centrally located myonuclei. During the maturation process, the myonuclei migrate to the periphery

Fig. 3

A switch from Notch to Wnt signaling is required for proper satellite cell differentiation. Satellite cells express high levels of Notch to retain them in a quiescent state, upon activation canonical Wnt signaling increases. The non-canonical Wnt7a drives the symmetric expansion of satellite stem cells and migration of satellite cells in general. Upon return to quiescence, satellite cells switch to Notch signaling, while Wnt7a drives the growth of already existing myotubes and myofibers, thereby inducing hypertrophy