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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

HFD suppresses the accumulation of PIP3 and IRS-1–associated PI3K activity in muscle during regeneration. A: At day 6 after injury, PIP3 was increased in regenerating muscles of mice fed a normal diet (ND); the HFD reduced PIP3 in uninjured and injured muscles (n = 6 in each group). B: In muscles of ND mice, IRS-1–associated PI3K activity was increased at day 6 after injury; the HFD significantly decreased this activity in uninjured and injured muscles (n = 6 in each group). C: In mice mice on a normal diet at 6 days after injury, Western blotting revealed a decrease in PTEN in regenerating myofibers. The HFD stimulated PTEN expression compared with results in mice on a normal diet (n = 6 in each group). CTX, cardiotoxin injury.
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Figure 3: HFD suppresses the accumulation of PIP3 and IRS-1–associated PI3K activity in muscle during regeneration. A: At day 6 after injury, PIP3 was increased in regenerating muscles of mice fed a normal diet (ND); the HFD reduced PIP3 in uninjured and injured muscles (n = 6 in each group). B: In muscles of ND mice, IRS-1–associated PI3K activity was increased at day 6 after injury; the HFD significantly decreased this activity in uninjured and injured muscles (n = 6 in each group). C: In mice mice on a normal diet at 6 days after injury, Western blotting revealed a decrease in PTEN in regenerating myofibers. The HFD stimulated PTEN expression compared with results in mice on a normal diet (n = 6 in each group). CTX, cardiotoxin injury.

Mentions: We examined insulin/IGF-1 signaling in regenerating muscles at day 6 after injury when histologic differences were present in HFD compared with normal diet mice. In mice fed the normal diet, PIP3 levels were increased in injured muscles compared with levels in uninjured muscles. Second, PIP3 levels in both uninjured and injured muscles were reduced compared with results in muscles of mice fed the normal diet (Fig. 3A). The mechanism for the lower levels of PIP3 associated with the HFD included suppression of IRS-1–associated PI3K activity in both uninjured and injured muscles compared with values in mice fed the normal diet (Fig. 3B). Besides reduced IRS-1–associated PI3K activity, PTEN expression was increased in both injured and uninjured muscles of HFD mice compared with results from mice fed the normal diet (Fig. 3C). The differences in PTEN expression were confirmed by immunostaining (supplemental Fig. 2B). Thus, at least two mechanisms could contribute to the HFD-induced decrease in PIP3 in regenerating muscle: a decrease in IRS-1–associated PI3K activity and an increase in PTEN expression.


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)

HFD suppresses the accumulation of PIP3 and IRS-1–associated PI3K activity in muscle during regeneration. A: At day 6 after injury, PIP3 was increased in regenerating muscles of mice fed a normal diet (ND); the HFD reduced PIP3 in uninjured and injured muscles (n = 6 in each group). B: In muscles of ND mice, IRS-1–associated PI3K activity was increased at day 6 after injury; the HFD significantly decreased this activity in uninjured and injured muscles (n = 6 in each group). C: In mice mice on a normal diet at 6 days after injury, Western blotting revealed a decrease in PTEN in regenerating myofibers. The HFD stimulated PTEN expression compared with results in mice on a normal diet (n = 6 in each group). CTX, cardiotoxin injury.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2874691&req=5

Figure 3: HFD suppresses the accumulation of PIP3 and IRS-1–associated PI3K activity in muscle during regeneration. A: At day 6 after injury, PIP3 was increased in regenerating muscles of mice fed a normal diet (ND); the HFD reduced PIP3 in uninjured and injured muscles (n = 6 in each group). B: In muscles of ND mice, IRS-1–associated PI3K activity was increased at day 6 after injury; the HFD significantly decreased this activity in uninjured and injured muscles (n = 6 in each group). C: In mice mice on a normal diet at 6 days after injury, Western blotting revealed a decrease in PTEN in regenerating myofibers. The HFD stimulated PTEN expression compared with results in mice on a normal diet (n = 6 in each group). CTX, cardiotoxin injury.
Mentions: We examined insulin/IGF-1 signaling in regenerating muscles at day 6 after injury when histologic differences were present in HFD compared with normal diet mice. In mice fed the normal diet, PIP3 levels were increased in injured muscles compared with levels in uninjured muscles. Second, PIP3 levels in both uninjured and injured muscles were reduced compared with results in muscles of mice fed the normal diet (Fig. 3A). The mechanism for the lower levels of PIP3 associated with the HFD included suppression of IRS-1–associated PI3K activity in both uninjured and injured muscles compared with values in mice fed the normal diet (Fig. 3B). Besides reduced IRS-1–associated PI3K activity, PTEN expression was increased in both injured and uninjured muscles of HFD mice compared with results from mice fed the normal diet (Fig. 3C). The differences in PTEN expression were confirmed by immunostaining (supplemental Fig. 2B). Thus, at least two mechanisms could contribute to the HFD-induced decrease in PIP3 in regenerating muscle: a decrease in IRS-1–associated PI3K activity and an increase in PTEN expression.

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