PrP^C 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; IRE1α, +195%, p < 0.001) while decreasing the level of mitochondrial biogenesis (SIRT-1, −50%, p < 0.01; PGC-1α, −36%, p < 0.05; VDAC, −27%, p < 0.001), and activated oxidative stress (serum myoglobin, +23%, p < 0.001; MDA, +23%, p < 0.05; NFκB, +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 (β-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 (PPARγ, +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.