PrP© Glycoprotein Is Indispensable for Maintenance of Skeletal Muscle Homeostasis During Aging

Background: The cellular prion protein (PrP (c)), a glycoprotein encoded by the PRNP gene, is known to modulate muscle mass and exercise capacity. However, the role of PrP (c) in the maintenance and regeneration of skeletal muscle during ageing remains unclear. Methods: This study investigated the change in PrP (c) expression during muscle formation using C2C12 cells and evaluated muscle function in Prnp wild-type (WT) and knock-out (KO) mice at different ages (1, 9 and 15 months). To determine the role of PrP (c) in skeletal muscle homeostasis during ageing, we conducted regeneration experiments via cardiotoxin injection in Prnp mice to assess the effects of PrP (c) deficiency on the senescence of satellite stem cells (SCs) and regenerative capacity in skeletal muscle. Results: Our data demonstrate that PrP (c) expression increased significantly during muscle differentiation (p < 0.01), correlating with myogenin (immunofluorescence at the differentiation stage). PrP (c) deficiency disrupted muscle homeostasis, leading to age-associated mitochondrial autophagy (Pink-1, +180%, p < 0.001; Parkin, +161%, p < 0.01) and endoplasmic reticulum stress (SERCA, -26%, p < 0.05; IRE1 alpha, +195%, p < 0.001) while decreasing the level of mitochondrial biogenesis (SIRT-1, -50%, p < 0.01; PGC-1 alpha, -36%, p < 0.05; VDAC, -27%, p < 0.001), and activated oxidative stress (serum myoglobin, +23%, p < 0.001; MDA, +23%, p < 0.05; NF kappa B, +117%, p < 0.05) during ageing, which accelerated reduced muscle growth or mass accumulation (tibialis anterior muscle mass, -23%, p < 0.001; gastrocnemius muscle mass, -30%, p < 0.001; muscle fibre size, -48%, p < 0.05; MSTN, +160%, p < 0.01; MAFbx, +83%, p < 0.05). Furthermore, PrP (c) deficiency induced the senescence (beta-galactosidase, +60%, p < 0.05; p16, +103%, p < 0.001) of SCs, which was directly related to the defect in muscle recovery, with the senescence-mediated enhancement of adipogenesis (PPAR gamma, +74%, p < 0.05) during the regeneration process after cardiotoxin-induced muscle injury. Conclusions: Our findings demonstrate that PrP (c) is indispensable for maintaining skeletal muscle homeostasis during ageing by modulating the functional integrity of mitochondria, ER and SCs.