Muscle Stem Cells and Exercise Training

Thomas J. Hawke

Disclosures

Exerc Sport Sci Rev. 2005;33(2):63-68. 

In This Article

Resident Muscle Stem Cell Populations

Adult skeletal muscle contains identifiable cell populations with stem cell-like characteristics. One of these cell populations, the myogenic progenitor cells (MPCs), are also known as satellite cells based on their location at the periphery of adult myofibers.[3] These undifferentiated progenitor cells are the most thoroughly characterized of the resident muscle stem cell populations. The MPCs are quiescent in the unstressed muscle, but can reenter the cell cycle (become activated) in response to signals associated with muscle damage. After activation, these cells will proliferate and migrate to the site of injury to repair or replace damaged myofibers by fusing together and/or fusing to existing myofibers (Fig. 1A)[6]

Myogenic progenitor cells mediate skeletal muscle regeneration and hypertrophy. (A) Quiescent myogenic progenitor cells (MPCs) reside in a peripheral location on the mature myofiber. In response to muscle damage, these cells will become activated, proliferate, and migrate to the site of injury. If the myofibers are extensively damaged, the MPCs will differentiate and fuse together to generate a new myofiber. Newly regenerated myofibers are identifiable based on their centrally located nuclei (top fiber). In response to hypertrophic stimuli, the MPCs will differentiate and fuse to existing myofibers, essentially donating their nuclei (bottom fiber). (B) The myonuclear domain theory suggests that the volume of cytoplasm managed by a nucleus within a myofiber is finite, such that any increases in myofiber cross-sectional area (hypertrophy) must be associated with a proportional increase in myonuclei. Evidence to date indicates that fusion of MPCs with the myofiber is responsible for the increase in myonuclei with hypertrophy. Note that the cross-sectional area within each of the triangles of the myofibers is similar.

The fusion of MPCs to existing myofibers is critical for large increases in myofiber cross-sectional area, and works on the premise of the myonuclear domain theory. This theory suggests that the myonucleus controls the production of mRNA and proteins for a finite volume of cytoplasm, such that increases in fiber size (hypertrophy) must be associated with a proportional increase in myonuclei, which are contributed from the MPC population (Fig. 1B). Importantly, the MPCs are self-renewing, such that a residual pool of these cells is reestablished after each discrete episode of muscle injury, and therefore capable of supporting additional rounds of regeneration. Whereas the MPC displays some similarities to other adult stem cell populations (such as self-renewal and a limited capacity to adopt alternative lineages), it is largely assumed that these cells are committed to the skeletal muscle lineage.

An additional population of cells with stem cell-like characteristics has recently been identified within numerous adult tissues, including skeletal muscle. These muscle stem cells can be isolated using dual-wavelength flow cytometric analysis (FACS) based on their ability to efflux the DNA dye, Hoechst 33342. Muscle stem cells isolated using FACS analyses are termed SP cells because they appear as a side population on the FACS profile (Fig. 2A). Muscle SP cells are far rarer than the MPCs within resting adult skeletal muscle (< 0.2 vs 2-5% of all muscle nuclei), and have been shown to display a greater ability to adopt other cell lineages (plasticity) than the MPC population.[7,11]

Muscle SP cells increase after injury, but are decreased in Foxk1 mutant skeletal muscle. (A) Representative FACS profile of muscle SP cells. Note that the SP cells are located in the gated region and account for 0.21% of the total cell population. (B) Inhibition of the SP cell phenotype after the addition of the Abcg2 inhibitor, FTC. (C) FACS profile reveals fewer SP cells in the Foxk1 mutant muscle compared to wild-type skeletal muscle. (D) Increased SP cell numbers (compared to uninjured skeletal muscle in panel A) are observed 5 d after injury of wild-type skeletal muscle. (E) Increased SP cell numbers (compared to uninjured Foxk1 mutant skeletal muscle) 5 d after cardiotoxin injury in Foxk1 mutant skeletal muscle. Note the increase in SP cell numbers in injured Foxk1 mutant skeletal muscle is less than injured wild-type skeletal muscle. (F) Quantitation of the SP cell numbers in wild-type and Foxk1 mutant injured skeletal muscle. Note that at each time period, wild-type skeletal muscle has increased numbers of SP cells (mean ± SEM). (Reprinted from Meeson, A.P., T.J. Hawke, S. Graham, N. Jiang, J. Eltermann, K. Hutcheson, J.M. DiMaio, T. Gallardo and D.J. Garry. Cellular and molecular regulation of skeletal muscle SP cells. Stem Cells 22:1305-1320, 2004. Copyright © 2004 AlphaMed Press 1066-6099. Used with permission.)

A number of studies have recently identified subpopulations within the muscle SP cell populations that display differential capacities for self-renewal, plasticity, proliferation, and differentiation.[4] Whether these subpopulations represent distinct cell populations, or whether they are the same cell population adapting to changes in their microenvironment, is still under investigation.

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