Connecting muscle development, birth defects, and evolution: An essential role for muscle connective tissue

Abstract

Skeletal muscle powers all movement of the vertebrate body and is distributed in multiple regions that have evolved distinct functions. Axial muscles are ancestral muscles essential for support and locomotion of the whole body. The evolution of the head was accompanied by development of cranial muscles essential for eye movement, feeding, vocalization, and facial expression. With the evolution of paired fins and limbs and their associated muscles, vertebrates gained increased locomotor agility, populated the land, and acquired fine motor skills. Finally, unique muscles with specialized functions have evolved in some groups, and the diaphragm which solely evolved in mammals to increase respiratory capacity is one such example. The function of all these muscles requires their integration with the other components of the musculoskeletal system: muscle connective tissue (MCT), tendons, bones as well as nerves and vasculature. MCT is muscle's closest anatomical and functional partner. Not only is MCT critical in the adult for muscle structure and function, but recently MCT in the embryo has been found to be crucial for muscle development. In this review, we examine the important role of the MCT in axial, head, limb, and diaphragm muscles for regulating normal muscle development, discuss how defects in MCT-muscle interactions during development underlie the etiology of a range of birth defects, and explore how changes in MCT development or communication with muscle may have led to the modification and acquisition of new muscles during vertebrate evolution.

Keywords: Axial muscle; Birth defects; Development; Diaphragm; Evolution; FAPs; Head; Limb; Muscle; Muscle connective tissue; Myogenesis.

Figure 1.. During the course of chordate and vertebrate evolution, axial and limb muscles become increasingly complex.

A-B. Simple axial muscles in Amphioxus (A) and tail of ascidian free-swimming larva (B) (based on Walker and Homberger, 1992). C. Lamprey myomeric axial muscle subdivided into epaxial muscle (red), innervated by dorsal roots, and hypaxial muscle (pink), innervated by ventral roots (based on Fetcho, 1987). D. Myomeric axial muscle of Chondrichythian, Actinopterygian, and Sarcopterygian fishes is subdivided into epaxial and hypaxial muscles innervated by dorsal and ventral roots, respectively, and separated by a horizontal septum (based on Romer and Parsons, 1986). E - F. Epaxial and hypaxial muscles of tetrapods, e.g. amphibians (E) and reptiles (F) are separated by vertebral transverse processes and subdivided into multiple muscles (based on Romer and Parsons, 1986). G. Simple shark ventral pectoral fin muscles extend from pectoral girdle to dermal rays (based on Walker and Homberger, 1992). H. Multiple ventral fin muscles of ray-finned perch extend pectoral girdle to bony rays (based on Winterbottom, 1974). I. Dorsal muscles of lungfish Neoceratodus pelvic fin are subdivided into two proximal-distal groups (after Diogo, Johnston, Molnar, Esteve-Altava 2016). J. Dorsal muscles of salamander Ambystoma subdivided into three proximal-distal groups (after Diogo et al., 2016). K. Dorsal and ventral muscles of grouse Dendragapus subdivided into three proximal-distal groups (after Kardon, 1998).

Figure 2.. Muscle and muscle connective tissue (MCT) structure, molecular markers, and development.

A – B. MCT surrounds myofibers, fascicles, and whole muscles to transmit contractile force of muscle to tendon and bone. C. During myogenesis muscle progenitors/stem cells (which express Pax3/7 in axial and limb muscles and variety of transcription factors in the head) become committed MyoD/Myf5+ myoblasts, differentiate into Myogenin+ myocytes, which fuse into post-mitotic, multinucleate myofibers. D. MCT fibroblasts (also known as FAPs in the adult) express Pdgfra, Tcf7l22, and Osr1 and secrete ECM.

Figure 3.. Development of axial muscles in tetrapods.

A. Epaxial muscle derives from the dorsomedial region of the dermomyotome and myotome, while the hypaxial muscle derives from the ventrolateral region of the dermomyotome and myotome. DML, dorsomedial lip and VLL, ventrolateral lip. B-C. Dorsomedial dermomyotome and myotome give rise to epaxial back muscles with MCT presumably derived from the somite (shown as red muscles outlined in grey). Hypaxial dermomyotome and myotome give rise to primaxial hypaxial muscles (e.g. intercostal muscles, pink muscles outlined in grey) with MCT presumably derived from the somite and also abaxial hypaxial muscles (e.g. abdominal muscles, pink muscles outlined in green) with MCT derived from lateral plate mesoderm (green).

Figure 4.. Development of cranial muscle in tetrapods.

(A) Transverse section through early head showing cranial neural crest migration and cranial mesoderm. (B) Transverse section through later developing head showing pharyngeal arch with a cranial mesodermal core surrounded by neural crest that has begun to infiltrate the mesoderm. (C) Groups of cranial muscles with their neural-crest derived MCT.

Figure 5.. Development of limb muscles in tetrapods.

A. Muscle progenitors (red) migrate from limb-level somites into the core of the limb, which contains attractive HGF and SDF signals, and avoids peripheral regions, which contains repulsive EphrinA5 signals. B. Muscle progenitors populate MCT (green) regions that express an array of transcription factors (Tbx3–5, Tcf4, Osr1, Hoxa11/d11) and tendon (blue) regions. C. Muscle progenitors that migrate into tendon regions do not differentiate, while those that migrate into MCT regions do differentiate. D-E. In MCT regions muscle progenitors differentiate, and so the MCT pattern pre-figures the future pattern of anatomical muscles. Tendons develop at the origin and insertion ends of forming muscles and their associated MCT.

Figure 6.. Development of the mammalian diaphragm.

A. Muscle progenitors (red) migrate from cervical somites to the pleuroperitoneal folds (PPFs, green). The PPFs are also the target for the axons of the phrenic nerve (orange). B-C. As PPFs spread dorsally and ventrally they carry the muscle progenitors, which differentiate into radially oriented myofibers. Outgrowth of phrenic nerves is also regulated by PPF expansion. D. PPFs give rise to the MCT guiding expansion and differentiation of muscle and ultimately surrounding myofibers of the costal diaphragm.