All for One and One for All: Regenerating Skeletal Muscle

Abstract

Despite the evolutionary loss of tissue regenerative potential, robust skeletal muscle repair processes are largely retained even in higher vertebrates. In mammals, the skeletal muscle regeneration program is driven by resident stem cells termed satellite cells, guided by the coordinated activity of multiple intrinsic and extrinsic factors and other cell types. A thorough understanding of muscle repair mechanisms is crucial not only for combating skeletal myopathies, but for its prospective aid in devising therapeutic strategies to endow regenerative potential on otherwise regeneration-deficient organs. In this review, we discuss skeletal muscle regeneration from an evolutionary perspective, summarize the current knowledge of cellular and molecular mechanisms, and highlight novel paradigms of muscle repair revealed by explorations of the recent decade.

Figure 1.

Evolutionary overview of cellular mechanisms of muscle regeneration. Two main strategies pertaining to the cellular origin of regenerated muscle have been employed by species to drive muscle regeneration. Dedifferentiation of mature muscle cells into proliferating myoblasts that redifferentiate to replace the damaged muscle is observed in some organisms. However, the majority of species use a stem cell–mediated regeneration response to reconstitute the injured musculature. Satellite cells, the muscle stem cells, differentiate and fuse to each other to generate a de novo myofiber, or fuse to an existing myofiber for repair.

Figure 2.

Multicellular control of muscle regeneration. The process of muscle regeneration involves the coordinated contribution of multiple cell types and associated intrinsic and extrinsic factors. The figure shows the primary events that take place in restoring muscle homeostasis following trauma and depicts the temporal involvement of the different cell types that culminate in successful repair.

Figure 3.

The diversity of satellite cells and stimuli that control skeletal muscle regeneration in various anatomical regions. The most studied Pax7⁺ satellite cells are present in all muscle groups including limb muscles and function to repair muscle after injury. Chemical injury of hindlimb skeletal muscle in the mouse is the classical muscle regeneration model. These satellite cells also contribute to muscle hypertrophy in response to increased load and are important for postnatal muscle growth. Satellite cells in the diaphragm and extraocular muscles (EOMs) are distinct, based on molecular markers and more constant activity, compared to satellite cells in the limb.