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.

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How to cite this article: Valenzuela PL, de Melo Aroeira AE, Torrella JR, de la Villa P. The effect of high-frequency neuromuscular electrical stimulation training on skeletal muscle properties in mice. Abstract:The aim of this study was to analyze the effects of high-frequency neuromuscular electrical stimulation training (NMES) on the structure, function and oxidative capacity of the skeletal muscle using a mice model (C57BL/6J strain, n=8). The left tibialis anterior muscle in mice was electro-stimulated (ST) whereas the right muscle was maintained as an internal control (CT). The ST limb was submitted to eight surface (100 Hz) NMES sessions in two weeks, with a minimum gap of 24 h between sessions. NMES training increased muscle mass (42.0±3.3 vs. 36.1±5.4 mg, p<0.05, effect size [ES] r=0.55), the mean fiber cross-sectional area (FCSA) (3318±333 vs. 2577±405 µ 2 , p<0.001, ES=0.71), maximal force (224.7±13.8 vs. 184.5±30.9 mN, p<0.01, ES=0.64), and the rate of force development (1.63±0.14 vs. 1.34±0.20 mN/ms, p<0.05, ES=0.64), with no effects on the muscle oxidative profile. These results demonstrate that surface NMES induced muscle hypertrophy and instigated an improvement in the contractile properties of the TA muscle in mice. Therefore, this animal model appears to be suitable for the study of hypertrophic processes as it enables better control of the stimulus properties (intensity, duration, frequency, etc.) than other traditionally used animal models and does not require negative reinforcements or surgical procedures.