Parvalbumin affects skeletal muscle trophism through modulation of mitochondrial calcium uptake

Abstract

Parvalbumin (PV) is a cytosolic Ca²⁺-binding protein highly expressed in fast skeletal muscle, contributing to an increased relaxation rate. Moreover, PV is an "atrogene" downregulated in most muscle atrophy conditions. Here, we exploit mice lacking PV to explore the link between the two PV functions. Surprisingly, PV ablation partially counteracts muscle loss after denervation. Furthermore, acute PV downregulation is accompanied by hypertrophy and upregulation by atrophy. PV ablation has a minor impact on sarcoplasmic reticulum but is associated with increased mitochondrial Ca²⁺ uptake, mitochondrial size and number, and contacts with Ca²⁺ release sites. Mitochondrial calcium uniporter (MCU) silencing abolishes the hypertrophic effect of PV ablation, suggesting that mitochondrial Ca²⁺ uptake is required for hypertrophy. In turn, an increase of mitochondrial Ca²⁺ is required to enhance expression of the pro-hypertrophy gene PGC-1α4, whose silencing blocks hypertrophy due to PV ablation. These results reveal how PV links cytosolic Ca²⁺ control to mitochondrial adaptations, leading to muscle mass regulation.

Keywords: calcium buffer; mitochondria; skeletal muscle.