Peroxisome proliferator-activated receptor β activation promotes myonuclear accretion in skeletal muscle of adult and aged mice

Giordano, Christian; Rousseau, A. S.; Wagner, Nicole; Gaudel, Céline; Murdaca, Joseph; Jehl-Piétri, Chantal; Sibille, Brigitte; Grimaldi, Paul A.; Lopez, Pascal

doi:10.1007/s00424-009-0676-9

Cited by 28 publications

(32 citation statements)

References 44 publications

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“…These data, together with previously published reports (19,23,51), strongly support a role for PPAR␤/␦ in positively regulating postnatal skeletal muscle growth. However, in contrast to the results presented here, previously published data from Dressel et al (44) describe that GW501516-mediated activation of PPAR␤/␦ does not affect myogenic differentiation of C2C12 myoblasts.…”

Section: Discussionsupporting

confidence: 86%

“…Pharmacological activation of the muscle-specific PPAR␤/␦ isoform promotes muscle development, myonuclear accretion, and satellite cell proliferation and restores sarcolemmal integrity in dystrophic mice models (17,19,23,50,51), strongly supporting a role for PPAR␤/␦ in regulating postnatal muscle growth and development. However, no study has yet clearly revealed the molecular mechanism(s) through which PPAR␤/␦ regulates skeletal muscle growth.…”

Section: Discussionmentioning

confidence: 93%

“…As a result, increased fatty acid oxidation, reduced fat accumulation in adipose tissue, and a lean phenotype is reported in mice (18). In addition, pharmacological activation of PPAR␤/␦ by GW0742 increases angiogenesis, enhances oxidative myofiber number, and improves myonuclear accretion in vivo (19), all features observed in response to exercise (20 -22). Furthermore, pharmacological activation of PPAR␤/␦ may act as a potential therapeutic in preventing the dramatic muscle wasting observed during muscular dystrophy (23).…”

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confidence: 99%

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Peroxisome Proliferator-activated Receptor β/δ Induces Myogenesis by Modulating Myostatin Activity

Bonala

Lokireddy

Harikumar

et al. 2012

Journal of Biological Chemistry

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Background: PPAR␤/␦ has been implicated in muscle regeneration; however the signaling mechanism(s) is unclear. Results: Activation of PPAR␤/␦-promoted Gasp-1 expression blocked myostatin activity and enhanced myogenesis. Conclusion: Activation of PPAR␤/␦ led to inhibition of myostatin activity and thus increased myogenesis. Significance: PPAR␤/␦ agonists are novel myostatin antagonists that have potential benefits toward improving postnatal muscle growth and repair.Classically, peroxisome proliferator-activated receptor ␤/␦ (PPAR␤/␦) function was thought to be restricted to enhancing adipocyte differentiation and development of adipose-like cells from other lineages. However, recent studies have revealed a critical role for PPAR␤/␦ during skeletal muscle growth and regeneration. Although PPAR␤/␦ has been implicated in regulating myogenesis, little is presently known about the role and, for that matter, the mechanism(s) of action of PPAR␤/␦ in regulating postnatal myogenesis. Here we report for the first time, using a PPAR␤/␦-specific ligand (L165041) and the PPAR␤/␦-null mouse model, that PPAR␤/␦ enhances postnatal myogenesis through increasing both myoblast proliferation and differentiation. In addition, we have identified Gasp-1 (growth and differentiation factor-associated serum protein-1) as a novel downstream target of PPAR␤/␦ in skeletal muscle. In agreement, reduced Gasp-1 expression was detected in PPAR␤/␦-null mice muscle tissue. We further report that a functional PPAR-responsive element within the 1.5-kb proximal Gasp-1 promoter region is critical for PPAR␤/␦ regulation of Gasp-1. Gasp-1 has been reported to bind to and inhibit the activity of myostatin; consistent with this, we found that enhanced secretion of Gasp-1, increased Gasp-1 myostatin interaction and significantly reduced myostatin activity upon L165041-mediated activation of PPAR␤/␦. Moreover, we analyzed the ability of hGASP-1 to regulate myogenesis independently of PPAR␤/␦ activation. The results revealed that hGASP-1 protein treatment enhances myoblast proliferation and differentiation, whereas silencing of hGASP-1 results in defective myogenesis. Taken together these data revealed that PPAR␤/␦ is a positive regulator of skeletal muscle myogenesis, which functions through negatively modulating myostatin activity via a mechanism involving Gasp-1.In the late 1960s, work performed by De Duve et al.(1) led to the identification of a series of compounds that promote peroxisome proliferation. These compounds were subsequently grouped into a family known as peroxisome proliferators. Peroxisome proliferators were shown to elicit biological function through binding to ligand-inducible nuclear hormone receptors, of which the first receptor, cloned from mouse liver, was termed peroxisome proliferator-activated receptor (PPAR) 2 (2). Upon ligand binding, PPARs become activated and bind to their target genes by forming heterodimeric complexes with retinoid-X receptors (RXR) (3, 4). The activated PPAR-RXR complex then binds to consensus peroxisome pr...

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Section: Discussionsupporting

confidence: 86%

Section: Discussionmentioning

confidence: 93%

mentioning

confidence: 99%

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Peroxisome Proliferator-activated Receptor β/δ Induces Myogenesis by Modulating Myostatin Activity

Bonala

Lokireddy

Harikumar

et al. 2012

Journal of Biological Chemistry

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“…In agreement with this, overexpression of a constitutively active PPAR␤/␦ in mouse skeletal muscle was found to induce differentiation of mitochondria-rich, oxidative type I muscle fibers (42). In addition, muscle-specific overexpression of PPAR␤/␦ has been shown to promote myonuclear density (13). PPAR␤/␦ also plays an important role in the adaptation of skeletal muscle to environmental changes, such as long-term fasting, by increasing the number of oxidative fibers (10).…”

mentioning

confidence: 48%

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

Chandrashekar

Manickam

et al. 2015

American Journal of Physiology-Endocrinology and Metabolism

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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.

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“…Increased myonuclear density has been found in transgenic muscle-specific over-expressing animals, as well as in wild-type mice treated for only 2 days with a PPARb agonist. As mouse aging is associated with reduced PPARb expression, and with decreased numbers of oxidative myofibres and myonuclei, which could be partially reversed by pharmacological PPARb activation, a potential use of PPARb agonists for the treatment of age-related muscle atrophy has been suggested [43].…”

Section: Discussionmentioning

confidence: 99%

CLA Reduces Inflammatory Mediators from A427 Human Lung Cancer Cells and A427 Conditioned Medium Promotes Differentiation of C2C12 Murine Muscle Cells

Oraldi¹,

Maggiora²,

Paiuzzi³

et al. 2012

Lipids

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Conjugated linoleic acid (CLA) is thought to have anti-proliferative and anti-inflammatory properties, but its effect on cancer cachexia is unknown. Two effects were here investigated: that of CLA on inflammatory mediator production in human lung cancer cells, and that of reduced mediators on the myogenic differentiation of murine muscle C2C12 cells. The latter cells were grown in medium conditioned by human lung cancer A427 cells, with or without CLA, to mimic only the effect of molecules released from the tumor ''in vivo'', excluding the effect of host-produced cachectic factors. The results obtained show that CLA was found to reduce the production of tumor necrosis factor-a, interleukin (IL)-1b and prostaglandin E2 (PGE2), but had no effect on IL-6 production. The mechanisms underlying the effect of CLA on cytokine or PGE2 release in A427 cells are probably mediated by activation of peroxisome proliferator-activated receptor (PPAR)a, which increased at 24 h CLA treatment. In turn, the reduced content of inflammatory mediators in medium conditioned by A427 cells, in the presence of CLA, allowed muscle cells to proliferate, again by inducing PPAR. The involvement of PPARa was demonstrated by treatment with the antagonist MK-886. The findings demonstrate the anti-inflammatory and myogenic action of CLA and point to its possible application as a novel dietary supplement and therapeutic agent in inflammatory disease states, such as cachexia.

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Peroxisome proliferator-activated receptor β activation promotes myonuclear accretion in skeletal muscle of adult and aged mice

Cited by 28 publications

References 44 publications

Peroxisome Proliferator-activated Receptor β/δ Induces Myogenesis by Modulating Myostatin Activity

Peroxisome Proliferator-activated Receptor β/δ Induces Myogenesis by Modulating Myostatin Activity

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

CLA Reduces Inflammatory Mediators from A427 Human Lung Cancer Cells and A427 Conditioned Medium Promotes Differentiation of C2C12 Murine Muscle Cells

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