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PTEN inhibition improves muscle regeneration in mice fed a high-fat diet.

Hu Z, Wang H, Lee IH, Modi S, Wang X, Du J, Mitch WE - Diabetes (2010)

Bottom Line: We also measured PIP(3) and the enzymes regulating its level, IRS-1-associated phosphatidylinositol 3-kinase (PI3K) and PTEN.These changes were independent of impaired proliferation of muscle progenitor or satellite cells but were principally related to increased expression of PTEN, which reduced PIP(3) in muscle.In cultured muscle cells, palmitate directly stimulated PTEN expression and reduced cell growth.

View Article: PubMed Central - PubMed

Affiliation: Nephrology Division, Baylor College of Medicine, Houston, Texas, USA. zhaoyonh@bcm.edu

ABSTRACT

Objective: Mechanisms impairing wound healing in diabetes are poorly understood. To identify mechanisms, we induced insulin resistance by chronically feeding mice a high-fat diet (HFD). We also examined the regulation of phosphatidylinositol 3,4,5-trisphosphate (PIP(3)) during muscle regeneration because augmented IGF-1 signaling can improve muscle regeneration.

Research design and methods: Muscle regeneration was induced by cardiotoxin injury, and we evaluated satellite cell activation and muscle maturation in HFD-fed mice. We also measured PIP(3) and the enzymes regulating its level, IRS-1-associated phosphatidylinositol 3-kinase (PI3K) and PTEN. Using primary cultures of muscle, we examined how fatty acids affect PTEN expression and how PTEN knockout influences muscle growth. Mice with muscle-specific PTEN knockout were used to examine how the HFD changes muscle regeneration.

Results: The HFD raised circulating fatty acids and impaired the growth of regenerating myofibers while delaying myofiber maturation and increasing collagen deposition. These changes were independent of impaired proliferation of muscle progenitor or satellite cells but were principally related to increased expression of PTEN, which reduced PIP(3) in muscle. In cultured muscle cells, palmitate directly stimulated PTEN expression and reduced cell growth. Knocking out PTEN restored cell growth. In mice, muscle-specific PTEN knockout improved the defects in muscle repair induced by HFD.

Conclusions: Insulin resistance impairs muscle regeneration by preventing myofiber maturation. The mechanism involves fatty acid-stimulated PTEN expression, which lowers muscle PIP(3). If similar pathways occur in diabetic patients, therapeutic strategies directed at improving the repair of damaged muscle could include suppression of PTEN activity.

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Related in: MedlinePlus

An HFD delays the recovery of and increases fibrosis in regenerating muscle. A: The weights of injured tibialis anterior muscles (normalized to the length of the tibia) were decreased in mice fed the HFD for 8 months. Muscles were obtained at 6, 12, 21, and 28 days after injury and compared with results from mice fed the normal diet (ND). n = 12 in each group. B: Hematoxylin-eosin sections of injured tibialis anterior muscles from HFD (right panel) and normal diet (left panel) mice revealed smaller regenerating myofibers (detected by their central nuclei). There also was an increase in interstitial space of muscle. The distribution of cross-sectional areas of new myofibers was shifted leftwards compared with values in mice fed a normal diet. C: Sirius red staining revealed an increase in collagen deposition at 12 (left panel) and 21 (right panel) days after injury in HFD mice. The collagen-containing area was significantly increased in muscles of HFD mice compared with results from muscles of mice on a normal diet (n = 6 in each group). *P < 0.01. d, days. (A high-quality digital representation of this figure is available in the online issue.)
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Figure 1: An HFD delays the recovery of and increases fibrosis in regenerating muscle. A: The weights of injured tibialis anterior muscles (normalized to the length of the tibia) were decreased in mice fed the HFD for 8 months. Muscles were obtained at 6, 12, 21, and 28 days after injury and compared with results from mice fed the normal diet (ND). n = 12 in each group. B: Hematoxylin-eosin sections of injured tibialis anterior muscles from HFD (right panel) and normal diet (left panel) mice revealed smaller regenerating myofibers (detected by their central nuclei). There also was an increase in interstitial space of muscle. The distribution of cross-sectional areas of new myofibers was shifted leftwards compared with values in mice fed a normal diet. C: Sirius red staining revealed an increase in collagen deposition at 12 (left panel) and 21 (right panel) days after injury in HFD mice. The collagen-containing area was significantly increased in muscles of HFD mice compared with results from muscles of mice on a normal diet (n = 6 in each group). *P < 0.01. d, days. (A high-quality digital representation of this figure is available in the online issue.)

Mentions: The HFD impaired regeneration of injured muscles: the weights of injured tibialis anterior muscles factored for tibia length were significantly lower than values from the mice fed a normal diet (Fig. 1A). On day 6 after injury, the sizes of regenerating myofibers (i.e., those with central nuclei) in muscles of HFD mice were smaller compared with values in mice fed the normal diet. At 12 and 21 days after injury, this pattern persisted (Fig. 1B; supplemental Fig. 1C).


PTEN inhibition improves muscle regeneration in mice fed a high-fat diet.

Hu Z, Wang H, Lee IH, Modi S, Wang X, Du J, Mitch WE - Diabetes (2010)

An HFD delays the recovery of and increases fibrosis in regenerating muscle. A: The weights of injured tibialis anterior muscles (normalized to the length of the tibia) were decreased in mice fed the HFD for 8 months. Muscles were obtained at 6, 12, 21, and 28 days after injury and compared with results from mice fed the normal diet (ND). n = 12 in each group. B: Hematoxylin-eosin sections of injured tibialis anterior muscles from HFD (right panel) and normal diet (left panel) mice revealed smaller regenerating myofibers (detected by their central nuclei). There also was an increase in interstitial space of muscle. The distribution of cross-sectional areas of new myofibers was shifted leftwards compared with values in mice fed a normal diet. C: Sirius red staining revealed an increase in collagen deposition at 12 (left panel) and 21 (right panel) days after injury in HFD mice. The collagen-containing area was significantly increased in muscles of HFD mice compared with results from muscles of mice on a normal diet (n = 6 in each group). *P < 0.01. d, days. (A high-quality digital representation of this figure is available in the online issue.)
© Copyright Policy - creative-commons
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2874691&req=5

Figure 1: An HFD delays the recovery of and increases fibrosis in regenerating muscle. A: The weights of injured tibialis anterior muscles (normalized to the length of the tibia) were decreased in mice fed the HFD for 8 months. Muscles were obtained at 6, 12, 21, and 28 days after injury and compared with results from mice fed the normal diet (ND). n = 12 in each group. B: Hematoxylin-eosin sections of injured tibialis anterior muscles from HFD (right panel) and normal diet (left panel) mice revealed smaller regenerating myofibers (detected by their central nuclei). There also was an increase in interstitial space of muscle. The distribution of cross-sectional areas of new myofibers was shifted leftwards compared with values in mice fed a normal diet. C: Sirius red staining revealed an increase in collagen deposition at 12 (left panel) and 21 (right panel) days after injury in HFD mice. The collagen-containing area was significantly increased in muscles of HFD mice compared with results from muscles of mice on a normal diet (n = 6 in each group). *P < 0.01. d, days. (A high-quality digital representation of this figure is available in the online issue.)
Mentions: The HFD impaired regeneration of injured muscles: the weights of injured tibialis anterior muscles factored for tibia length were significantly lower than values from the mice fed a normal diet (Fig. 1A). On day 6 after injury, the sizes of regenerating myofibers (i.e., those with central nuclei) in muscles of HFD mice were smaller compared with values in mice fed the normal diet. At 12 and 21 days after injury, this pattern persisted (Fig. 1B; supplemental Fig. 1C).

Bottom Line: We also measured PIP(3) and the enzymes regulating its level, IRS-1-associated phosphatidylinositol 3-kinase (PI3K) and PTEN.These changes were independent of impaired proliferation of muscle progenitor or satellite cells but were principally related to increased expression of PTEN, which reduced PIP(3) in muscle.In cultured muscle cells, palmitate directly stimulated PTEN expression and reduced cell growth.

View Article: PubMed Central - PubMed

Affiliation: Nephrology Division, Baylor College of Medicine, Houston, Texas, USA. zhaoyonh@bcm.edu

ABSTRACT

Objective: Mechanisms impairing wound healing in diabetes are poorly understood. To identify mechanisms, we induced insulin resistance by chronically feeding mice a high-fat diet (HFD). We also examined the regulation of phosphatidylinositol 3,4,5-trisphosphate (PIP(3)) during muscle regeneration because augmented IGF-1 signaling can improve muscle regeneration.

Research design and methods: Muscle regeneration was induced by cardiotoxin injury, and we evaluated satellite cell activation and muscle maturation in HFD-fed mice. We also measured PIP(3) and the enzymes regulating its level, IRS-1-associated phosphatidylinositol 3-kinase (PI3K) and PTEN. Using primary cultures of muscle, we examined how fatty acids affect PTEN expression and how PTEN knockout influences muscle growth. Mice with muscle-specific PTEN knockout were used to examine how the HFD changes muscle regeneration.

Results: The HFD raised circulating fatty acids and impaired the growth of regenerating myofibers while delaying myofiber maturation and increasing collagen deposition. These changes were independent of impaired proliferation of muscle progenitor or satellite cells but were principally related to increased expression of PTEN, which reduced PIP(3) in muscle. In cultured muscle cells, palmitate directly stimulated PTEN expression and reduced cell growth. Knocking out PTEN restored cell growth. In mice, muscle-specific PTEN knockout improved the defects in muscle repair induced by HFD.

Conclusions: Insulin resistance impairs muscle regeneration by preventing myofiber maturation. The mechanism involves fatty acid-stimulated PTEN expression, which lowers muscle PIP(3). If similar pathways occur in diabetic patients, therapeutic strategies directed at improving the repair of damaged muscle could include suppression of PTEN activity.

Show MeSH
Related in: MedlinePlus