Regulation of postnatal skeletal muscle growth and metabolism by peroxisome proliferator-activated receptorβ/δ

• Main Author: Chandrashekar, Preeti
• Other Authors: Walter Wahli
• Format: Theses and Dissertations
• Language: English
• Published: 2016
• Subjects: DRNTU::Science::Biological sciences
• Online Access: https://hdl.handle.net/10356/67320
• Institution: Nanyang Technological University

PPARβ/δ is ubiquitously expressed, however higher levels of PPARβ/δ are observed in skeletal muscle. Recently our laboratory showed that PPARβ/δ modulates Myostatin activity to induce myogenesis in skeletal muscle. Extending on from this previous work here we have investigated the role of PPARβ/δ in postnatal muscle growth and aging. Our results show that PPARβ/δ-null mice display reduced body weight, skeletal muscle weight and myofibre 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. Consistent with this hypothesis, immunohistochemical analysis on regenerating muscle revealed an increased inflammatory response and reduced myoblast proliferation. Histological analysis confirmed that the regenerated muscle fibres of PPARβ/δ-null mice maintained an atrophy phenotype with reduced numbers of centrally placed nuclei. Even though satellite cell numbers were reduced prior to injury, satellite cell self-renewal was found to be unaffected in PPARβ/δ-null mice after regeneration. Previously we showed that inactivation of PPARβ/δ increases myostatin signaling and inhibits myogenesis. Our results here confirm that inactivation of myostatin signaling rescues the atrophy phenotype and improves muscle fibre cross-sectional area in both uninjured and regenerated TA 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, we also demonstrate that functional antagonism of myostatin has utility in rescuing these effects. Since our study revealed that PPARβ/δ plays an important role in postnatal myogenesis, we next investigated whether or not deletion of PPARβ/δ affected aging related muscle wasting, termed Sarcopenia. Histological analysis revealed that there was enhanced myofibre atrophy at 3, 12 and 24- months of age and a significant reduction in myofibre number at 24-months of age in PPARβ/δ-null mice. In addition, we also observed reduced grip strength in PPARβ/δ-null mice at 18 months of age along with a significant reduction in satellite cell number at 6 and 24 months. Since PPARβ/δ has been shown to influence oxidative muscle fibre number, we next investigated if deletion of PPARβ/δ influenced mitochondrial number and function in skeletal muscle. Our results show that PPARβ/δ-null muscle had remarkably reduced oxidative potential as assessed through SDH staining of TA muscle. Furthermore, a significant reduction in mitochondrial DNA content was also observed at 12 months of age in PPARβ/δ-null mice skeletal muscle. In addition, we observed reduced maximal respiration rate and spare respiratory capacity of mitochondria in differentiated myotubes cultured from aged PPARβ/δ-null mice. Molecular analysis further indicated that the reduced mitochondrial number in PPARβ/δ-null muscle could be due to enhanced mitophagy as PPARβ/δ-null mice displayed increased expression of the autophagy/mitophagy markers LC3, Parkin and Mul1 together with reduced expression of the Mul1 target Mfn2 in skeletal muscle at 12-months of age. Collectively, these data suggest that the premature muscle atrophy seen in young adult PPARβ/δ-null mice could be due to enhanced mitophagy. In conclusion, we propose that PPARβ/δ expression is essential for proper postnatal development of skeletal muscle and that lack of PPARβ/δ results in reduced satellite cell number and poor regeneration. Furthermore, inactivation of PPARβ/δ could lead to enhanced mitophagy and premature wasting of skeletal muscle underscoring the benefits of PPARβ/δ agonists in alleviating aging-related muscle atrophy.