Periostin is temporally expressed as an extracellular matrix component in skeletal muscle regeneration and differentiation

Highlights

• Periostin expression was compared in acute and chronic muscle degeneration models.

• Periostin is temporally expressed in the myofibers of the regenerating muscle tissue.

• Periostin expression is documented in in vitro models of muscle differentiation.

• Periostin expression in regeneration deduced tissue remodeling but not fibrosis.

• Genomic structure and splicing pattern of rodent periostin gene are documented.

Abstract

The transcriptional events and pathways responsible for the acquisition of the myogenic phenotype during regeneration and myogenesis have been studied extensively. The modulators that shape the extracellular matrix in health and disease, however, are less understood. Understanding the components and pathways of this remodeling will aid the restoration of the architecture and prevent deterioration under pathological conditions such as fibrosis. Periostin, a matricellular protein associated with remodeling of the extracellular matrix and connective tissue architecture, is emerging in pathological conditions associated with fibrosis in adult life. Periostin also complicates fibrosis in degenerative skeletal muscle conditions such as dystrophies. This study primarily addresses the spatial and temporal involvement of periostin along skeletal muscle regeneration. In the acute skeletal muscle injury model that shows recovery without fibrosis, we show that periostin is rapidly disrupted along with the extensive necrosis and periostin mRNA is transiently upregulated during the myotube maturation. This expression is stringently initiated from the newly regenerating fibers. However, this observation is contrasting to a model that displays extensive fibrosis where upregulation of periostin expression is stable and confined to the fibrotic compartments of endomysial and perimysial space. In vitro myoblast differentiation further supports the claim that upregulation of periostin expression is a function of extracellular matrix remodeling during myofiber differentiation and maturation. We further seek to identify the expression kinetics of various periostin isoforms during the differentiation of rat and mouse myoblasts. Results depict that a singular periostin isoform dominated the rat muscle, contrasting to multiple isoforms in C2C12 myoblast cells. This study shows that periostin, a mediator with deleterious impact on conditions exhibiting fibrosis, is also produced and secreted by myoblasts and regenerating myofibers during architectural remodeling in the course of development and regeneration.

Introduction

Under physiological conditions, skeletal muscle exhibits a stable structure. However, in the case of injury, satellite cells – the resident somatic stem cells of the muscle – are activated to restore structural integrity (Charge and Rudnicki, 2004). Differentiation and repair both pursue cascade of transcriptional events harmonized by common myogenic regulatory factors (MRFs) and signaling pathways (Braun and Gautel, 2011). The transcriptional events responsible for the acquisition of the myogenic phenotype are relatively well understood. Repeated cycles of injury and regeneration impact the tissue architecture of the skeletal muscle, causing fibrosis, fatty infiltration and myofibrillary atrophy, which are the three hallmarks of chronic muscle degeneration. The molecular events that shape the extracellular matrix and cause fibrosis under pathological conditions, such as the dystrophies, aging or disuse atrophy are still obscure.

High throughput technologies provide insights into the transcriptional events that characterize differentiation, repair and adaptive response of the tissue. Using the open-access transcriptome data, we conducted an in silico survey to pinpoint a conjoint list of genes that were significantly altered in a set of transcriptome observations commonly targeting physiologic and pathologic conditions of skeletal muscle. These include time-course profiling of myoblast differentiation (Moran et al., 2002, Tomczak et al., 2004, Chen et al., 2006), various human skeletal muscle pathologies (Bakay et al., 2006), dystrophin-deficient (mdx) mouse diaphragm (Porter et al., 2004) and sarcopenia model in rat (Wang et al., 2012). This approach accentuated a number of commonly altered soluble or exported factors, including periostin. Periostin is a matricellular protein which is ubiquitously expressed during embryonic morphogenesis in the extracellular matrix and connective tissues. It is directly interacting with collagen and fibronectin during fibrillogenesis in early development (Kudo, 2011). In the postnatal life, periostin is abundant in connective tissues exposed to mechanical strains such as tendon, bone, heart valves and skin (Merle and Garnero, 2012). However, periostin upregulation is associated with fibrotic pathological conditions such as scar formation in wound healing, crash-induced bone damage, myocardial infarcts, pulmonary fibrosis, liver cirrhosis and fibrosis of the skeletal muscle (Hamilton, 2008, Rani et al., 2009, Dobaczewski et al., 2010, Merle and Garnero, 2012).

An attributed function promoting collagen cross-linking is the association of periostin to pathologic fibrotic events (Maruhashi et al., 2010). In skeletal muscle, periostin function is linked to fibrosis-related conditions such as strain injury evoked by eccentric exercise (Rani et al., 2009). Periostin knockout animals exhibit diminished fibroblastic proliferation in the course of cardiac recovery from myocardial infarction (Oka et al., 2007, Norris et al., 2009). Likewise, diminished fibrosis and enhanced myofiber regeneration are observed in knockout dystrophic mice (Lorts et al., 2012). Besides its role in chronic degenerative conditions, the abovementioned transcriptome results primed us to investigate the spatial and temporal expression of periostin in various models of muscle regeneration and myoblast differentiation.