Lack of type XV collagen causes a skeletal myopathy and cardiovascular defects in mice

Abstract

Type XV collagen occurs widely in the basement membrane zones of tissues, but its function is unknown. To understand the biological role of this protein, a null mutation in the Col15a1 gene was introduced into the germ line of mice. Despite the complete lack of type XV collagen, the mutant mice developed and reproduced normally, and they were indistinguishable from their wild-type littermates. However, Col15a1-deficient mice showed progressive histological changes characteristic for muscular diseases after 3 months of age, and they were more vulnerable than controls to exercise-induced muscle injury. Despite the antiangiogenic role of type XV collagen-derived endostatin, the development of the vasculature appeared normal in the null mice. Nevertheless, ultrastructural analyses revealed collapsed capillaries and endothelial cell degeneration in the heart and skeletal muscle. Furthermore, perfused hearts showed a diminished inotropic response, and exercise resulted in cardiac injury, changes that mimic early or mild heart disease. Thus, type XV collagen appears to function as a structural component needed to stabilize skeletal muscle cells and microvessels.T ype XV collagen belongs to the heterogeneous group of non-fibril-forming collagens and is thought to be a homotrimer consisting of three ␣1(XV) collagen chains (1). It is characterized by a central highly interrupted triple helical domain and large N-and C-terminal noncollagenous domains (2-4), and it has been shown to be a chondroitin sulfate proteoglycan (5). Type XV collagen mRNAs are expressed in many tissues, but the highest mRNA levels in the mouse can be detected in the heart and skeletal muscle (4). The protein is shown by immunostaining to have a widespread tissue distribution and has been localized mainly to the basement membrane zones, although it can also be found in the fibrillar collagen matrix of some tissues (6, 7). Its function is not known, however.In terms of primary structure, type XV collagen is highly homologous with type XVIII collagen, and together they form a distinct subgroup among the collagens (1, 3). They have thrombospondin-1 sequence homology in the N terminus, seven homologous collagenous domains, and highly homologous Cterminal noncollagenous domains. Type XVIII collagen is the precursor of endostatin, which has been shown to have a potent antiangiogenic effect (8), and the highest degree of homology between collagen types XV and XVIII involves the C-terminal endostatin sequence. The corresponding fragment in type XV collagen has also been shown to have antiangiogenic activity (9, 10).To understand the biological function and significance of type XV collagen, we generated a mouse strain lacking in ␣1(XV) collagen chains by site-specific Cre-loxP-mediated deletion in embryonic stem (ES) cells (11). The data suggest a structural role for type XV collagen in providing mechanical stability between cells and the extracellular matrix in skeletal muscle fibers and microvessels. Col15a1 deficiency leads to functional rather than struct...

Large-scale analysis of the human and mouse transcriptomes

“…Primary sequence comparisons of the mouse and human collagen XV genes revealed that the mouse harbors seven collagenous domains to nine for the human gene (23). In addition, although the conserved C-terminal endostatin domain predicts a role in angiogenesis, inactivation of the mouse structural gene by homologous recombination revealed a normal vasculature (24). Taken in sum, these data support the hypothesis that the physiological role of collagen XV is different between the two species.…”

The multiple functions of collagen XVIII in development and disease

“…Human diseases due to mutations in the collagen XV gene are not known, but mice lacking this collagen have a mild myopathic phenotype, with impaired cardiac and microvascular structure and function (Eklund et al, 2001;Rasi et al, 2010). Thus despite the high structural similarities between collagens XVIII and XV, they have entirely different biological roles.…”

The influence of extracellular matrix derived from skeletal muscle tissue on the proliferation and differentiation of myogenic progenitor cells ex vivo

“…Proliferation of MPCs generates myoblasts that undergo several rounds of division before fusing to form myofibers, which comprise the basic cellular unit of skeletal muscle. During skeletal muscle regeneration, ECM molecules play a key role in the proliferation of MPCs and myoblasts as well as the subsequent stages of differentiation required to form new myofibers [11][12][13][14][15][16][17]. The study of skeletal muscle ECM regulation of MPC and myoblast behavior presents a significant challenge.…”