Inactivation of PPARβ/δ adversely affects satellite cells and reduces postnatal myogenesis

Abstract

Peroxisome proliferator-activated receptor β/δ ( PPARβ/δ) is a ubiquitously expressed gene with higher levels observed in skeletal muscle. Recently, our laboratory showed (Bonala S, Lokireddy S, Arigela H, Teng S, Wahli W, Sharma M, McFarlane C, Kambadur R. J Biol Chem 287: 12935–12951, 2012) that PPARβ/δ modulates myostatin activity to induce myogenesis in skeletal muscle. In the present study, we show that PPARβ/δ-null mice display reduced body weight, skeletal muscle weight, and myofiber atrophy during postnatal development. In addition, a significant reduction in satellite cell number was observed in PPARβ/δ-null mice, suggesting a role for PPARβ/δ in muscle regeneration. To investigate this, tibialis anterior muscles were injured with notexin, and muscle regeneration was monitored on days 3, 5, 7, and 28 postinjury. Immunohistochemical analysis revealed an increased inflammatory response and reduced myoblast proliferation in regenerating muscle from PPARβ/δ-null mice. Histological analysis confirmed that the regenerated muscle fibers of PPARβ/δ-null mice maintained an atrophy phenotype with reduced numbers of centrally placed nuclei. Even though satellite cell numbers were reduced before injury, satellite cell self-renewal was found to be unaffected in PPARβ/δ-null mice after regeneration. Previously, our laboratory had showed (Bonala S, Lokireddy S, Arigela H, Teng S, Wahli W, Sharma M, McFarlane C, Kambadur R. J Biol Chem 287: 12935–12951, 2012) that inactivation of PPARβ/δ increases myostatin signaling and inhibits myogenesis. Our results here indeed confirm that inactivation of myostatin signaling rescues the atrophy phenotype and improves muscle fiber cross-sectional area in both uninjured and regenerated tibialis anterior muscle from PPARβ/δ-null mice. Taken together, these data suggest that absence of PPARβ/δ leads to loss of satellite cells, impaired skeletal muscle regeneration, and postnatal myogenesis. Furthermore, our results also demonstrate that functional antagonism of myostatin has utility in rescuing these effects.

An aPPARent Functional Consequence in Skeletal Muscle Physiology via Peroxisome Proliferator-Activated Receptors

“…The specific ablation of PPARβ/δ in the mouse satellite cells has been reported, with approximately 40% fewer satellite cells than their wild-type littermates [ 156 ]. A similar observation was also reported in total PPARβ/δ-knock out mice [ 157 ]. Mice with PPARβ/δ-deficient muscle progenitor cells exhibited impaired muscle regeneration after cardiotoxin-induced injury and exhibited reduced growth kinetics and proliferation in primary cultures [ 156 ].…”

“…Mice with PPARβ/δ-deficient muscle progenitor cells exhibited impaired muscle regeneration after cardiotoxin-induced injury and exhibited reduced growth kinetics and proliferation in primary cultures [ 156 ]. Furthermore, these mice developed metabolic syndrome upon aging, similar to the PPARβ/δ knockout mice [ 43 , 156 , 157 ]. The authors found reduced foxhead box protein (FOXO1) expression in quiescent PPARβ/δ-deficient satellite cells, which impaired the proliferation and differentiation ability of these satellite cells during muscle regeneration, thus suggesting that PPARβ/δ regulates the regenerative capability of skeletal muscle through FOXO1 [ 156 ].…”

Asymmetric expression of H19 and ADIPOQ in concave/convex paravertebral muscles is associated with severe adolescent idiopathic scoliosis

“…1b ). It is interesting to note that several genes related with PPAR signaling pathway, such as PCK1, FABP4, SCD, PLIN1, ADIPOQ, MSTN, showed a higher expression in the concave side of the paravertebral muscles, since PPAR signaling pathway plays a major regulatory role in postnatal myogenesis and muscle fiber type (Wang et al 2004 ; Chandrashekar et al 2015 ).…”

Annexin A1 Deficiency does not Affect Myofiber Repair but Delays Regeneration of Injured Muscles

“…Based on these findings, we analyzed the role of Anx A1 in myoblast fusion in vivo during the initial days of the post-injury muscle regeneration. Published reports on muscle regeneration quantify this process by monitoring the following: a) expression of different myogenic differentiation markers at different times post-injury 43 ; b) the size of unregenerated (necrotic) areas in the muscle section 44 , and the number of newly formed (regenerated) myofibers 45 . In addition to employing all of these metrics, to specifically assess the extent of cell-cell fusion without being affected by the proliferation and myogenic commitment of the satellite cells, we also used a combination of different end points to assess myoblast differentiation and fusion.…”