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Aging and disease    2018, Vol. 9 Issue (5) : 769-784     DOI: 10.14336/AD.2017.1214
Orginal Article |
Hyperphosphatemia Promotes Senescence of Myoblasts by Impairing Autophagy Through Ilk Overexpression, A Possible Mechanism Involved in Sarcopenia

Patricia Sosa1, Elena Alcalde-Estevez1,2, Patricia Plaza1, Nuria Troyano1, Cristina Alonso3, Laura Martínez-Arias4, Andresa Evelem de Melo Aroeira1, Diego Rodriguez-Puyol2,5,6, Gemma Olmos1,6, *, Susana López-Ongil2,6, #, María P. Ruíz-Torres1,6, #

1System Biology Department, Alcala University, Alcalá de Henares, Madrid, Spain.
2Research Unit, Biomedical Research Foundation from Príncipe de Asturias University Hospital, Alcalá de Henares, Madrid, Spain.
3Geriatric and Frailty Section, Getafe University Hospital, Getafe, Madrid, Spain.
4Bone and Mineral Research Unit, Hospital Universitario Central de Asturias. Instituto de Investigación Sanitaria del Principado de Asturias, Red de Investigación Renal (REDinREN] del ISCIII, Oviedo, Spain
5Nephrology Section, Biomedical Research Foundation from Principe de Asturias University Hospital, Alcalá de Henares, Madrid, Spain
6Instituto Reina Sofía de Investigación Nefrológica, IRSIN, Madrid, Spain.
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Abstract  

In mammalians, advancing age is associated with sarcopenia, the progressive and involuntary loss of muscle mass and strength. Hyperphosphatemia is an aging-related condition involved in several pathologies. The aim of this work was to assess whether hyperphosphatemia plays a role in the age-related loss of mass muscle and strength by inducing cellular senescence in murine myoblasts and to explore the intracellular mechanism involved in this effect. Cultured mouse C2C12 cells were treated with 10 mM beta-glycerophosphate (BGP] at different periods of time to induce hyperphosphatemia. BGP promoted cellular senescence after 24 h of treatment, assessed by the increased expression of p53, acetylated-p53 and p21 and senescence associated β-galactosidase activity. In parallel, BGP increased ILK expression and activity, followed by mTOR activation and autophagy reduction. Knocking-down ILK expression increased autophagy and protected cells from senescence induced by hyperphosphatemia. BGP also reduced the proliferative capacity of cultured myoblasts. Old mice (24-months-old] presented higher serum phosphate concentration, lower forelimb strength, higher expression of p53 and ILK and less autophagy in vastus muscle than young mice (5-months-old]. In conclusion, we propose that hyperphosphatemia induces senescence in cultured myoblasts through ILK overexpression, reducing their proliferative capacity, which could be a mechanism involved in the development of sarcopenia, since old mice showed loss of muscular strength correlated with high serum phosphate concentration and increased levels of ILK and p53.

Keywords hyperphosphatemia      senescence      myoblasts      ILK      autophagy      sarcopenia     
Corresponding Authors: Olmos Gemma   
About author: These authors contributed equally to this work.
Issue Date: 12 September 2017
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Sosa Patricia
Alcalde-Estevez Elena
Plaza Patricia
Troyano Nuria
Alonso Cristina
Martínez-Arias Laura
Evelem de Melo Aroeira Andresa
Rodriguez-Puyol Diego
Olmos Gemma
López-Ongil Susana
Ruíz-Torres María P.
Cite this article:   
Sosa Patricia,Alcalde-Estevez Elena,Plaza Patricia, et al. Hyperphosphatemia Promotes Senescence of Myoblasts by Impairing Autophagy Through Ilk Overexpression, A Possible Mechanism Involved in Sarcopenia[J]. Aging and disease, 2018, 9(5): 769-784.
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http://www.aginganddisease.org/EN/10.14336/AD.2017.1214     OR     http://www.aginganddisease.org/EN/Y2018/V9/I5/769
Figure 1.  Hyperphosphatemia induces senescence in C<sub>2</sub>C<sub>12</sub> cells

Cultured C2C12 were treated with 10 mM BGP for 24, 48, 72 and 96 hours. A) Acetylated-p53 (Ac-p53), p53 and p21 expression were analysed by western blot. A representative blot is shown in each case. Bar graphs represent the densitometric analysis of the bands. The results are expressed as a percentage of control cells (time 0h) and are the mean ± standard error of the mean from five different experiments. * p< 0.05 vs control). B) Senescence associated β-galactosidase activity was analysed by confocal microscopy using the fluorogenic substrate C12FDG after 24, 48 and 72 hours 10 mM BGP incubation. C) C2C12 were treated with 10 mM BGP or vehicle for 48 hours in the presence or the absence of phosphonoformic acid (0.5 mM, PFA) and senescence associated β-galactosidase activity was evaluated as above. In B and C) A representative experiment is shown in each case. Bar graphs represent the densitometric analysis of the fluorescence of 20 cells. Results are expressed as arbitrary fluorescence intensity units and are the mean ± standard error of the mean from five different experiments. * p< 0.05 vs control. ** p<0.05 vs BGP.

Figure 2.  Hyperphosphatemia induces senescence by increasing ILK expression and activity

A) C2C12 were treated with 10 mM BGP for 24 or 48 hours, then, ILK, phospho-GSK3β (pGSK-3ß) and total GSK3β were analysed by western blot. B and C) C2C12 were transfected with the specific siRNA against ILK (siILK) or unspecific siRNA as a control (scramble) and treated for 48 hours with 10 mM BGP. ILK (B) and p53 (C) expression was evaluated by western blot. A representative blot is shown in each case. Bar graphs represent the densitometric analysis of the bands. The results are expressed as a percentage of control and are the mean ± standard error of the mean from four different experiments. * p< 0.05 vs control. D) C2C12 were transfected with the specific siRNA against ILK (siILK) or unspecific siRNA as a control (scramble) and treated for 48 hours with 10 mM BGP. Senescence associated β-galactosidase activity was analysed by confocal microscopy using the fluorogenic substrate C12FDG. Bar graph represents the densitometric analysis of the fluorescence of 20 cells. Results are expressed as arbitrary fluorescence intensity units and are the mean ± standard error of the mean from four different experiments. * p< 0.05 vs control.

Figure 3.  Hyperphosphatemia activates mTOR and reduces autophagy in myoblast through ILK activation

A, B and D) C2C12 cells were incubated with 10 mM BGP for 24 or 48 hours, and with or without chloroquine (CQ, 20μM, 4h) (C). Phospho-S6 (pS6), the mTOR substrate, and total S6 (S6) (A), ratio LC3II/LC3I (B and C) and p62 (D) protein expression were evaluated by western blot. A representative blot is shown in each case. Bar graphs represent the densitometric analysis of the bands. The results are expressed as a percentage of control and are the mean ± standard error of the mean from four different experiments. * p< 0.05 vs control. E and F) C2C12 were transfected with the specific siRNA against ILK (silLK) or unspecific siRNA as a control (Sc, scramble) and treated for 48 hours with 10 mM BGP. Then, ILK and pS6 (E) and ILK and p62 (F) were analysed by western blot. A representative blot is shown in each case. Bar graphs represent the densitometric analysis of the bands. The results are expressed as a percentage of control and are the mean ± standard error of the mean from five different experiments. * p< 0.05 vs control.

Figure 4.  Inhibition of mTOR with rapamycin increases autophagy and protects myoblast from BGP-induced senescence

C2C12 cells were treated with 10 mM BGP in the presence or the absence of 50 nM Rapamycin for 48 hours. Phospho-S6 expression (pS6) (A), LC3II/LC3I ratio and p62 expression (B) and p53 expression (C) were analysed by western blot. A representative blot is shown in each case. Bar graphs represent the densitometric analysis of the bands. The results are expressed as a percentage of control and are the mean ± standard error of the mean from five different experiments. * p< 0.05 vs control. D) C2C12 were treated with 48 hours with 10 mM BGP in the presence or the absence of 50 nM rapamycin. Senescence associated β-galactosidase activity was analysed by confocal microscopy using the fluorogenic substrate C12FDG. Bar graph represents the densitometric analysis of the fluorescence of 20 cells. Results are expressed as arbitrary fluorescence intensity units are the mean ± standard error of the mean from four different experiments. *p< 0.05 vs control.

Figure 5.  Hyperphosphatemia reduces proliferation of myoblasts

A) C2C12 growing in DMEM supplemented with 10% FBS were treated with 10 mM BGP or vehicle for 48 hours. After that, confluent monolayers were scratch wounded. Photographs of wounds were captured at 0, 20 and 24 hours post-wounding to determine the degree of wound closure. A representative experiment is shown. Graphs represent the percentage of control (time 0 h) wound area at different times post-wounding. Results are mean ± SEM from five experiments. * p=0.021 between control and BGP treatment. B) C2C12 were grown in DMEM with (10%) or without (0%) FBS and with 10 mM BGP for 48 hours. BrdU incorporation during the following 24 hours was evaluated by flow cytometry. Bar graph represents the percentage of proliferating cells with respect to the control cells growing in DMEM without FBS. Results are mean ± SEM from six experiments. * p < 0.05 vs control 0%. C) C2C12 cells were grown in DMEM supplemented with 10% FBS and treated with 10 mM BGP for 24 and 48 hours. PCNA expression was evaluated by western blot. A representative blot is shown. Bar graph represents the densitometric analysis of the bands. The results are expressed as a percentage of control and are the mean ± SEM from five different experiments. * p< 0.05 vs control.

Figure 6.  Hyperphosphatemia impairs myogenic differentiation of myoblasts

C2C12 were grown with 2% horse serum for 48, 72 and 168 hours to promote myogenic differentiation. A) Myosin heavy chain (MHC, red) and desmin (green) were analysed by immunofluorescence with specific antibodies using a confocal microscopy. B) MHC positive cells were counted and represented in a bar graph. Results are mean ± SEM from three experiments. * p< 0.05 vs control 48 h. #p<0.001 vs control at the same time. C) MHC expression was evaluated by western blot. A representative blot is shown. Bar graphs represent the densitometric analysis of the bands. Results are mean ± SEM from three experiments. * p< 0.05 vs control 48 h. #p<0.001 vs control at the same time.

Figure 7.  Aged mice present elevated serum phosphate linked to higher expression of ILK and senescence genes and loss of muscle strength

Twenty-four-month-old mice (Old) were compared with five-month-old ones (Young). A) Serum phosphate concentration was assessed by a colorimetric method. Graph represents the mean ± SEM from values obtained from 10 animals per group. * p< 0.05 vs young. B-D) p53 (B), ILK (C) and p62 (D) expression was evaluated by western blot in protein extracts isolated from vastus from old and young mice. A representative blot is shown in each case. Bar graphs represent the densitometric analysis of the bands. The results are expressed as a percentage of young mice and are the mean ± SEM from ten animals per group. * p< 0.05 vs young. E) Forelimb grip strength test was performed in young and old mice. Results are mean ± SEM from ten animals per group. * p< 0.05 vs young.

Figure 8.  Hyperphosphatemia increases proinflammatory cytokine expression in C<sub>2</sub>C<sub>12</sub>

Cultured C2C12 were treated with 10 mM BGP for 24, 48 and 72 hours. Total mRNA was isolated and IL6 (A), TNF-α (B) and MCP-1 (C) mRNA expression was evaluated by RT-qPCR. Results are expressed as fold change respect to control. * p<0.05 vs control

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