Hanging on for the ride: Adhesion to the extracellular matrix mediates cellular responses in skeletal muscle morphogenesis and disease

Abstract

Skeletal muscle specification and morphogenesis during early development are critical for normal physiology. In addition to mediating locomotion, skeletal muscle is a secretory organ that contributes to metabolic homeostasis. Muscle is a highly adaptable tissue, as evidenced by the ability to increase muscle cell size and/or number in response to weight bearing exercise. Conversely, muscle wasting can occur during aging (sarcopenia), cancer (cancer cachexia), extended hospital stays (disuse atrophy), and in many genetic diseases collectively known as the muscular dystrophies and myopathies. It is therefore of great interest to understand the cellular and molecular mechanisms that mediate skeletal muscle development and adaptation. Muscle morphogenesis transforms short muscle precursor cells into long, multinucleate myotubes that anchor to tendons via the myotendinous junction. This process requires carefully orchestrated interactions between cells and their extracellular matrix microenvironment. These interactions are dynamic, allowing muscle cells to sense biophysical, structural, organizational, and/or signaling changes within their microenvironment and respond appropriately. In many musculoskeletal diseases, these cell adhesion interactions are disrupted to such a degree that normal cellular adaptive responses are not sufficient to compensate for accumulating damage. Thus, one major focus of current research is to identify the cell adhesion mechanisms that drive muscle morphogenesis, with the hope that understanding how muscle cell adhesion promotes the intrinsic adaptability of muscle tissue during development may provide insight into potential therapeutic approaches for muscle diseases. Our objectives in this review are to highlight recent studies suggesting conserved roles for cell-extracellular matrix adhesion in vertebrate muscle morphogenesis and cellular adaptive responses in animal models of muscle diseases.

Coordinated development of the limb musculoskeletal system: Tendon and muscle patterning and integration with the skeleton

“…To date, there is still very little known about how the muscle-tendon attachment (myotendinous junction, MTJ) is formed or how these tissues find each other in the limb, especially since limb muscles do not induce tendon progenitors (Charvet et al, 2012). Although there has been some progress defining the role of the extracellular matrix in general MTJ development, much of this work was carried out in tissues other than limb (Goody et al, 2015; Kraft-Sheleg et al, 2016). This section will therefore focus on the development of the tendon-bone insertion with emphasis on recent data that have dramatically improved our understanding of this tissue.…”

Tmem2 regulates cell-matrix interactions that are essential for muscle fiber attachment

“…Establishment and maintenance of muscle fiber attachment at the MTJ require successful interactions with the ECM molecules that compose the basement membrane (Goody et al, 2015;Snow and Henry, 2009). Moreover, the MZtmem2 phenotype shares some characteristics with the phenotypes of laminin-deficient and fibronectin-deficient embryos, including the presence of fibers that cross the MTJ (Snow et al, 2008a,b), prompting us to investigate the ECM in MZtmem2 mutants.…”

“…Since fiber attachment also relies upon effective CMAC assembly (Goody et al, 2010(Goody et al, , 2015Jackson and Ingham, 2013), we investigated whether the MTJ defects in MZtmem2 mutants are restricted to the basement membrane or are also reflected in the n=6; MZtmem2, n=4; Mtmem2 expressing full-length tmem2 ('+full'), n=6; MZtmem2+full, n=8; Mtmem2 expressing tmem2 ectodomain ('+ecto'), n=2; MZtmem2+ecto, n=5]. Introduction of either full-length Tmem2 or the Tmem2 ectodomain into MZtmem2 mutants caused improvement in fiber attachment.…”

“…As muscle precursors mature, they elongate to form fibers that span each segment and attach to the somite boundaries (Goody et al, 2015). Attachments are created through direct interactions of muscle fibers with the extracellular matrix (ECM), and sites of attachment develop into the myotendinous junction (MTJ), which transmits muscular forces to the skeletal system (Charvet et al, 2012).…”

“…Several protein complexes are known to play primary roles in connecting muscle cells to the MTJ (Charvet et al, 2012;Goody et al, 2015;Thorsteinsdóttir et al, 2011). Within the ECM, deposition of both fibrillar fibronectin and polymerized laminin is crucial for successful anchoring of muscle fibers.…”