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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.

SUBMITTER: Butera G

PROVIDER: S-EPMC8113653 | biostudies-literature | 2021 May

REPOSITORIES: biostudies-literature

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Parvalbumin affects skeletal muscle trophism through modulation of mitochondrial calcium uptake.

Butera Gaia G Vecellio Reane Denis D Canato Marta M Pietrangelo Laura L Boncompagni Simona S Protasi Feliciano F Rizzuto Rosario R Reggiani Carlo C Raffaello Anna A

Cell reports 20210501 5

Parvalbumin (PV) is a cytosolic Ca<sup>2+</sup>-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 ...[more]

PMID: 33951435

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Project description:As muscle contraction requires ATP and Ca(2+), skeletal muscle function is highly dependent on communication between two major intracellular organelles: mitochondria and sarcoplasmic reticulum (SR). In adult skeletal muscle, mitochondria located within the I-band of the sarcomere are connected to the SR by small ?10 nm electron dense tethers that bridge the outer mitochondrial membrane to the region of SR that is ?130 nm from the site of Ca(2+) release. However, the molecular composition of tethers and their precise impact on mitochondrial Ca(2+) uptake in skeletal muscle is unclear. Mitofusin-2 (Mfn2) is a transmembrane GTPase present in both mitochondria and ER/SR membranes that forms trans-dimers and participates in mitochondrial fusion. Here we evaluated the role Mfn2 plays in mitochondrial morphology, localization, and functional SR-mitochondrial Ca(2+) crosstalk in adult skeletal muscle. Compared to a non-targeting (CTRL) siRNA, in vivo electroporation of 400 nM Mfn2 siRNA (Mfn2 KD) into mouse footpads resulted in a marked acute reduction (67±3%) in Mfn2 protein levels in flexor digitorum brevis (FDB) muscles that occurred without a change in other key Ca(2+) regulatory proteins. Electron microscopy analyses revealed that Mfn2 knockdown resulted in a change in mitochondria morphology and mis-localization of some mitochondria from the I-band to the A-band region of the sarcomere. To assess the role of Mfn2 in SR-mitochondrial crosstalk, we measured mitochondrial Ca(2+) uptake and myoplasmic Ca(2+) transients with rhod-2 and mag-fluo-4, respectively, during repetitive high frequency tetanic stimulation (5×100 Hz tetani, 500 ms/tetani, 0.2 duty cycle) in CTRL and Mfn2 KD fibers. Mitochondrial Ca(2+) uptake during repetitive tetanic stimulation was significantly reduced (40%) in Mfn2 KD FDB fibers, which was accompanied by a parallel elevation in the global electrically evoked myoplasmic Ca(2+) transient. Mfn2 KD also resulted in a reduction of the mitochondrial membrane potential, which contributed to the observed decrease in activity-dependent mitochondrial Ca(2+) uptake. Consistent with this idea, a similar decrease in mitochondrial Ca(2+) uptake was also observed in wild type fibers following a comparable reduction in mitochondrial membrane potential induced by acute exposure to a low concentration (50 nM) of carbonylcyanide-p-trifluoromethoxyphenylhydrazone (FCCP). In addition, both global and mitochondrial Ca(2+) transients during repetitive tetanic stimulation were similarly reduced by both slow (EGTA) and fast (BAPTA) Ca(2+) chelating agents. Together, these results indicate that Mfn2 promotes proper mitochondrial morphology, localization, and membrane potential required for optimal activity-dependent mitochondrial Ca(2+) uptake and buffering of the global myoplasmic Ca(2+) transient in adult skeletal muscle.

Dataset Information

Parvalbumin affects skeletal muscle trophism through modulation of mitochondrial calcium uptake.

Publications

Parvalbumin affects skeletal muscle trophism through modulation of mitochondrial calcium uptake.

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