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Myogenin regulates exercise capacity but is dispensable for skeletal muscle regeneration in adult mdx mice.

Meadows E, Flynn JM, Klein WH - PLoS ONE (2011)

Bottom Line: Unexpectedly, we found that myogenin was dispensable for muscle regeneration.Factors associated with muscle fatigue, metabolism, and proteolysis were significantly altered in mdx:Myog-deleted mice, and this might contribute to their increased exercise capacity.Our results reveal novel functions for myogenin in adult muscle and suggest that reducing Myog expression in other muscle disease models may partially restore muscle function.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry and Molecular Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.

ABSTRACT
Duchenne muscular dystrophy (DMD) is the most prevalent inherited childhood muscle disorder in humans. mdx mice exhibit a similar pathophysiology to the human disorder allowing for an in-depth investigation of DMD. Myogenin, a myogenic regulatory factor, is best known for its role in embryonic myogenesis, but its role in adult muscle maintenance and regeneration is still poorly understood. Here, we generated an mdx:Myog(flox/flox) mouse harboring a tamoxifen-inducible Cre recombinase transgene, which was used to conditionally delete Myog during adult life. After tamoxifen treatment, three groups of mice were created to study the effects of Myog deletion: mdx:Myog(flox/flox) mice (mdx), Myog(flox/flox) mice (wild-type), and mdx:Myog(floxΔ/floxΔ):Cre-ER mice (mdx:Myog-deleted). mdx:Myog-deleted mice exhibited no adverse phenotype and behaved normally. When run to exhaustion, mdx:Myog-deleted mice demonstrated an enhanced capacity for exercise compared to mdx mice, running nearly as far as wild-type mice. Moreover, these mice showed the same signature characteristics of muscle regeneration as mdx mice. Unexpectedly, we found that myogenin was dispensable for muscle regeneration. Factors associated with muscle fatigue, metabolism, and proteolysis were significantly altered in mdx:Myog-deleted mice, and this might contribute to their increased exercise capacity. Our results reveal novel functions for myogenin in adult muscle and suggest that reducing Myog expression in other muscle disease models may partially restore muscle function.

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Altered expression of nNOS in mdx, mdx:Myog-deleted, and wild-type hindlimb muscle.RT-qPCR analysis demonstrated that transcript levels of nNOS were reduced in mdx mice (n = 3). Expression of nNOS was increased 2.2-fold in mdx:Myog-deleted mice (n = 3) compared to that in mdx mice. Error bars represent 1 standard deviation (*p<0.05).
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pone-0016184-g008: Altered expression of nNOS in mdx, mdx:Myog-deleted, and wild-type hindlimb muscle.RT-qPCR analysis demonstrated that transcript levels of nNOS were reduced in mdx mice (n = 3). Expression of nNOS was increased 2.2-fold in mdx:Myog-deleted mice (n = 3) compared to that in mdx mice. Error bars represent 1 standard deviation (*p<0.05).

Mentions: To begin elucidating the mechanisms that are responsible for the enhanced exercise performance observed in mdx:Myog-deleted mice, we determined the transcript levels of genes whose expression might be expected to change in the absence of myogenin. Using RT-qPCR, we determined the transcript levels of genes that regulate muscle development, metabolic processes, and muscle proteolysis, namely, Myf5, MyoD, Mrf4, nNOS, PFK, Hdac4, glycogen synthetase, and muscle glycogen phosphorylase. In the light of recent findings showing that Trim63 and Fbxo32 are regulated by myogenin and promote muscle proteolysis and atrophy, we examined the expression of these genes [21]. Of these, the expression of Fbxo32 was significantly decreased 1.2 fold (data not shown) while the expression of nNOS increased 2.2 fold in gastrocnemius muscle of mdx:Myog-deleted mice compared to that of mdx mice (Figure 8). Changes in nNOS expression might have contributed to the enhanced exercise endurance capacity seen in mdx:Myog-deleted mice over their mdx counterparts. These alterations in gene expression suggest a mechanistic basis for this observed physiologic phenomenon.


Myogenin regulates exercise capacity but is dispensable for skeletal muscle regeneration in adult mdx mice.

Meadows E, Flynn JM, Klein WH - PLoS ONE (2011)

Altered expression of nNOS in mdx, mdx:Myog-deleted, and wild-type hindlimb muscle.RT-qPCR analysis demonstrated that transcript levels of nNOS were reduced in mdx mice (n = 3). Expression of nNOS was increased 2.2-fold in mdx:Myog-deleted mice (n = 3) compared to that in mdx mice. Error bars represent 1 standard deviation (*p<0.05).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3021523&req=5

pone-0016184-g008: Altered expression of nNOS in mdx, mdx:Myog-deleted, and wild-type hindlimb muscle.RT-qPCR analysis demonstrated that transcript levels of nNOS were reduced in mdx mice (n = 3). Expression of nNOS was increased 2.2-fold in mdx:Myog-deleted mice (n = 3) compared to that in mdx mice. Error bars represent 1 standard deviation (*p<0.05).
Mentions: To begin elucidating the mechanisms that are responsible for the enhanced exercise performance observed in mdx:Myog-deleted mice, we determined the transcript levels of genes whose expression might be expected to change in the absence of myogenin. Using RT-qPCR, we determined the transcript levels of genes that regulate muscle development, metabolic processes, and muscle proteolysis, namely, Myf5, MyoD, Mrf4, nNOS, PFK, Hdac4, glycogen synthetase, and muscle glycogen phosphorylase. In the light of recent findings showing that Trim63 and Fbxo32 are regulated by myogenin and promote muscle proteolysis and atrophy, we examined the expression of these genes [21]. Of these, the expression of Fbxo32 was significantly decreased 1.2 fold (data not shown) while the expression of nNOS increased 2.2 fold in gastrocnemius muscle of mdx:Myog-deleted mice compared to that of mdx mice (Figure 8). Changes in nNOS expression might have contributed to the enhanced exercise endurance capacity seen in mdx:Myog-deleted mice over their mdx counterparts. These alterations in gene expression suggest a mechanistic basis for this observed physiologic phenomenon.

Bottom Line: Unexpectedly, we found that myogenin was dispensable for muscle regeneration.Factors associated with muscle fatigue, metabolism, and proteolysis were significantly altered in mdx:Myog-deleted mice, and this might contribute to their increased exercise capacity.Our results reveal novel functions for myogenin in adult muscle and suggest that reducing Myog expression in other muscle disease models may partially restore muscle function.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry and Molecular Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.

ABSTRACT
Duchenne muscular dystrophy (DMD) is the most prevalent inherited childhood muscle disorder in humans. mdx mice exhibit a similar pathophysiology to the human disorder allowing for an in-depth investigation of DMD. Myogenin, a myogenic regulatory factor, is best known for its role in embryonic myogenesis, but its role in adult muscle maintenance and regeneration is still poorly understood. Here, we generated an mdx:Myog(flox/flox) mouse harboring a tamoxifen-inducible Cre recombinase transgene, which was used to conditionally delete Myog during adult life. After tamoxifen treatment, three groups of mice were created to study the effects of Myog deletion: mdx:Myog(flox/flox) mice (mdx), Myog(flox/flox) mice (wild-type), and mdx:Myog(floxΔ/floxΔ):Cre-ER mice (mdx:Myog-deleted). mdx:Myog-deleted mice exhibited no adverse phenotype and behaved normally. When run to exhaustion, mdx:Myog-deleted mice demonstrated an enhanced capacity for exercise compared to mdx mice, running nearly as far as wild-type mice. Moreover, these mice showed the same signature characteristics of muscle regeneration as mdx mice. Unexpectedly, we found that myogenin was dispensable for muscle regeneration. Factors associated with muscle fatigue, metabolism, and proteolysis were significantly altered in mdx:Myog-deleted mice, and this might contribute to their increased exercise capacity. Our results reveal novel functions for myogenin in adult muscle and suggest that reducing Myog expression in other muscle disease models may partially restore muscle function.

Show MeSH
Related in: MedlinePlus