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Effects of pleiotrophin overexpression on mouse skeletal muscles in normal loading and in actual and simulated microgravity.

Camerino GM, Pierno S, Liantonio A, De Bellis M, Cannone M, Sblendorio V, Conte E, Mele A, Tricarico D, Tavella S, Ruggiu A, Cancedda R, Ohira Y, Danieli-Betto D, Ciciliot S, Germinario E, Sandonà D, Betto R, Camerino DC, Desaphy JF - PLoS ONE (2013)

Bottom Line: PTN overexpression did not prevent soleus muscle atrophy, slow-to-fast transition, and capillary regression induced by SF and HU.The numerous effects of PTN on muscle gene expression and functional parameters demonstrate the sensitivity of muscle fibers to the cytokine.Although little benefit was found in HU muscle disuse, PTN may emerge useful in various muscle diseases, because it exerts synergetic actions on muscle fibers and vessels, which could enforce oxidative metabolism and ameliorate muscle performance.

View Article: PubMed Central - PubMed

Affiliation: Section of Pharmacology, Department of Pharmacy & Drug Sciences, University of Bari - Aldo Moro, Bari, Italy.

ABSTRACT
Pleiotrophin (PTN) is a widespread cytokine involved in bone formation, neurite outgrowth, and angiogenesis. In skeletal muscle, PTN is upregulated during myogenesis, post-synaptic induction, and regeneration after crushing, but little is known regarding its effects on muscle function. Here, we describe the effects of PTN on the slow-twitch soleus and fast-twitch extensor digitorum longus (EDL) muscles in mice over-expressing PTN under the control of a bone promoter. The mice were maintained in normal loading or disuse condition, induced by hindlimb unloading (HU) for 14 days. Effects of exposition to near-zero gravity during a 3-months spaceflight (SF) into the Mice Drawer System are also reported. In normal loading, PTN overexpression had no effect on muscle fiber cross-sectional area, but shifted soleus muscle toward a slower phenotype, as shown by an increased number of oxidative type 1 fibers, and increased gene expression of cytochrome c oxidase subunit IV and citrate synthase. The cytokine increased soleus and EDL capillary-to-fiber ratio. PTN overexpression did not prevent soleus muscle atrophy, slow-to-fast transition, and capillary regression induced by SF and HU. Nevertheless, PTN exerted various effects on sarcolemma ion channel expression/function and resting cytosolic Ca(2+) concentration in soleus and EDL muscles, in normal loading and after HU. In conclusion, the results show very similar effects of HU and SF on mouse soleus muscle, including activation of specific gene programs. The EDL muscle is able to counterbalance this latter, probably by activating compensatory mechanisms. The numerous effects of PTN on muscle gene expression and functional parameters demonstrate the sensitivity of muscle fibers to the cytokine. Although little benefit was found in HU muscle disuse, PTN may emerge useful in various muscle diseases, because it exerts synergetic actions on muscle fibers and vessels, which could enforce oxidative metabolism and ameliorate muscle performance.

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Cytosolic Ca2+ concentration at rest in Sol (A) and EDL (B) muscle fibers of wild-type and PTN-overexpressing mice after 14 days HU.The cytosolic Ca2+ concentration was determined in mechanically-dissociated muscle fibers with cytofluorescent imaging technique using the Ca2+ dye FURA-2. Each bar is the mean ± SEM calculated from 13-to-47 muscle fibers of 2-to-3 mice. Statistical analysis performed with unpaired Student’s t test indicates significant change (P<0.05) versus WT-G (*), WT-HU ($), and PTN-G (#).
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pone-0072028-g006: Cytosolic Ca2+ concentration at rest in Sol (A) and EDL (B) muscle fibers of wild-type and PTN-overexpressing mice after 14 days HU.The cytosolic Ca2+ concentration was determined in mechanically-dissociated muscle fibers with cytofluorescent imaging technique using the Ca2+ dye FURA-2. Each bar is the mean ± SEM calculated from 13-to-47 muscle fibers of 2-to-3 mice. Statistical analysis performed with unpaired Student’s t test indicates significant change (P<0.05) versus WT-G (*), WT-HU ($), and PTN-G (#).

Mentions: The cytosolic calcium ion concentration at rest (restCa) depends on muscle phenotype, being higher in fibers of slow-twitch Sol muscle compared to fast-twitch EDL or gastrocnemius muscles [30]. We previously demonstrated that HU reduces restCa in Sol muscle fibers of rats and mice, in accord with the slow-to-fast shift of muscle phenotype [14], [18]. In the present study, restCa was 1.66 times higher in Sol muscle fibers compared to EDL muscle fibers of WT mice maintained in ground conditions (Fig. 6). As expected, restCa was significantly reduced by about 35% in WT Sol muscle fibers after HU, whereas no effect was found in EDL muscle fibers. In Sol muscle fibers, PTN over-expression did not affect restCa in ground conditions, nor the HU-dependent reduction. In EDL muscle fibers, PTN overexpression significantly increased restCa by 21%, whereas a reduction of about 50% was found after hindlimb unloading.


Effects of pleiotrophin overexpression on mouse skeletal muscles in normal loading and in actual and simulated microgravity.

Camerino GM, Pierno S, Liantonio A, De Bellis M, Cannone M, Sblendorio V, Conte E, Mele A, Tricarico D, Tavella S, Ruggiu A, Cancedda R, Ohira Y, Danieli-Betto D, Ciciliot S, Germinario E, Sandonà D, Betto R, Camerino DC, Desaphy JF - PLoS ONE (2013)

Cytosolic Ca2+ concentration at rest in Sol (A) and EDL (B) muscle fibers of wild-type and PTN-overexpressing mice after 14 days HU.The cytosolic Ca2+ concentration was determined in mechanically-dissociated muscle fibers with cytofluorescent imaging technique using the Ca2+ dye FURA-2. Each bar is the mean ± SEM calculated from 13-to-47 muscle fibers of 2-to-3 mice. Statistical analysis performed with unpaired Student’s t test indicates significant change (P<0.05) versus WT-G (*), WT-HU ($), and PTN-G (#).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3756024&req=5

pone-0072028-g006: Cytosolic Ca2+ concentration at rest in Sol (A) and EDL (B) muscle fibers of wild-type and PTN-overexpressing mice after 14 days HU.The cytosolic Ca2+ concentration was determined in mechanically-dissociated muscle fibers with cytofluorescent imaging technique using the Ca2+ dye FURA-2. Each bar is the mean ± SEM calculated from 13-to-47 muscle fibers of 2-to-3 mice. Statistical analysis performed with unpaired Student’s t test indicates significant change (P<0.05) versus WT-G (*), WT-HU ($), and PTN-G (#).
Mentions: The cytosolic calcium ion concentration at rest (restCa) depends on muscle phenotype, being higher in fibers of slow-twitch Sol muscle compared to fast-twitch EDL or gastrocnemius muscles [30]. We previously demonstrated that HU reduces restCa in Sol muscle fibers of rats and mice, in accord with the slow-to-fast shift of muscle phenotype [14], [18]. In the present study, restCa was 1.66 times higher in Sol muscle fibers compared to EDL muscle fibers of WT mice maintained in ground conditions (Fig. 6). As expected, restCa was significantly reduced by about 35% in WT Sol muscle fibers after HU, whereas no effect was found in EDL muscle fibers. In Sol muscle fibers, PTN over-expression did not affect restCa in ground conditions, nor the HU-dependent reduction. In EDL muscle fibers, PTN overexpression significantly increased restCa by 21%, whereas a reduction of about 50% was found after hindlimb unloading.

Bottom Line: PTN overexpression did not prevent soleus muscle atrophy, slow-to-fast transition, and capillary regression induced by SF and HU.The numerous effects of PTN on muscle gene expression and functional parameters demonstrate the sensitivity of muscle fibers to the cytokine.Although little benefit was found in HU muscle disuse, PTN may emerge useful in various muscle diseases, because it exerts synergetic actions on muscle fibers and vessels, which could enforce oxidative metabolism and ameliorate muscle performance.

View Article: PubMed Central - PubMed

Affiliation: Section of Pharmacology, Department of Pharmacy & Drug Sciences, University of Bari - Aldo Moro, Bari, Italy.

ABSTRACT
Pleiotrophin (PTN) is a widespread cytokine involved in bone formation, neurite outgrowth, and angiogenesis. In skeletal muscle, PTN is upregulated during myogenesis, post-synaptic induction, and regeneration after crushing, but little is known regarding its effects on muscle function. Here, we describe the effects of PTN on the slow-twitch soleus and fast-twitch extensor digitorum longus (EDL) muscles in mice over-expressing PTN under the control of a bone promoter. The mice were maintained in normal loading or disuse condition, induced by hindlimb unloading (HU) for 14 days. Effects of exposition to near-zero gravity during a 3-months spaceflight (SF) into the Mice Drawer System are also reported. In normal loading, PTN overexpression had no effect on muscle fiber cross-sectional area, but shifted soleus muscle toward a slower phenotype, as shown by an increased number of oxidative type 1 fibers, and increased gene expression of cytochrome c oxidase subunit IV and citrate synthase. The cytokine increased soleus and EDL capillary-to-fiber ratio. PTN overexpression did not prevent soleus muscle atrophy, slow-to-fast transition, and capillary regression induced by SF and HU. Nevertheless, PTN exerted various effects on sarcolemma ion channel expression/function and resting cytosolic Ca(2+) concentration in soleus and EDL muscles, in normal loading and after HU. In conclusion, the results show very similar effects of HU and SF on mouse soleus muscle, including activation of specific gene programs. The EDL muscle is able to counterbalance this latter, probably by activating compensatory mechanisms. The numerous effects of PTN on muscle gene expression and functional parameters demonstrate the sensitivity of muscle fibers to the cytokine. Although little benefit was found in HU muscle disuse, PTN may emerge useful in various muscle diseases, because it exerts synergetic actions on muscle fibers and vessels, which could enforce oxidative metabolism and ameliorate muscle performance.

Show MeSH
Related in: MedlinePlus