Deficiency in parvalbumin increases fatigue resistance in fast-twitch muscle and upregulates mitochondria

Abstract

The soluble Ca2+-binding protein parvalbumin (PV) is expressed at high levels in fast-twitch muscles of mice. Deficiency of PV in knockout mice (PV -/-) slows down the speed of twitch relaxation, while maximum force generated during tetanic contraction is unaltered. We observed that PV-deficient fast-twitch muscles were significantly more resistant to fatigue than were the wild type. Thus components involved in Ca2+ homeostasis during the contraction-relaxation cycle were analyzed. No upregulation of another cytosolic Ca2+-binding protein was found. Mitochondria are thought to play a physiological role during muscle relaxation and were thus analyzed. The fractional volume of mitochondria in the fast-twitch muscle extensor digitorum longus (EDL) was almost doubled in PV -/- mice, and this was reflected in an increase of cytochrome c oxidase. A faster removal of intracellular Ca2+ concentration ([Ca2+]i) 200-700 ms after fast-twitch muscle stimulation observed in PV -/- muscles supports the role for mitochondria in late [Ca2+]i removal. The present results also show a significant increase of the density of capillaries in EDL muscles of PV -/- mice. Thus alterations in the dynamics of Ca2+ transients detected in fast-twitch muscles of PV -/- mice might be linked to the increase in mitochondria volume and capillary density, which contribute to the greater fatigue resistance of these muscles.

Ectopic parvalbumin expression in mouse forebrain neurons increases excitotoxic injury provoked by ibotenic acid injection into the striatum

“…Semiquantitative Western blot analysis of the mitochondrial protein COXI (Chen et al, 2001) was done in the forebrain of mice and confirmed our morphometric mitochondria data. In samples of mice ectopically expressing neuronal PV, the signal for COXI was weaker as compared to that from WT (Fig.…”

“…Differences in COXI signal intensities were of smaller magnitude than changes in fractional area of neuronal mitochondria, as the whole tissue homogenate used to obtain the protein fraction contains not only neurons expressing the transgene, but also glial cells, endothelial cells, etc. It has recently been shown that in PV-knockout mice, mitochondria in fast-twitch muscles are up-regulated (Chen et al, 2001), indicating that in the absence of a diffusible buffer, mitochondria contribute to Ca 2+ buffering. A similar up-regulation also occurs in Purkinje cells of PV-KO mice, suggesting that a close link between PV levels and mitochondria volume is not restricted to muscle cells (B. Schwaller, in preparation).…”

Deficiency in parvalbumin, but not in calbindin D-28k upregulates mitochondrial volume and decreases smooth endoplasmic reticulum surface selectively in a peripheral, subplasmalemmal region in the soma of Purkinje cells

“…Mitochondria participate in Ca 2ϩ removal during muscle relaxation in slow-twitch (Sembrowich et al, 1985;Gillis, 1997) and fast-twitch muscles (Rudolf et al, 2004); in neurons they also contribute to the presynaptic regulation of Ca 2ϩ transients (Billups and Forsythe, 2002). Besides the anticipated slowing of muscle relaxation in PVϪ/Ϫ mice, a twofold increase in mitochondrial volume density is observed that is viewed as a specific homeostatic compensation mechanism (Chen et al, 2001). Interestingly, the biochemical composition of PVϪ/Ϫ fast-muscle mitochondria is as found in slow-twitch muscles, characterized by higher expression levels of proteins involved in oxidative phosphorylation (Racay et al, 2006).…”

“…Such changes did not occur at the level of other Ca 2ϩ -binding proteins (CaBPs) (Schmidt et al, 2003b), but involved morphological alterations. An increase in PC spine length and volume was specifically induced by elimination of CB (Vecellio et al, 2000), while elimination of PV in fast-twitch muscles led to an approximately twofold increase in the mitochondrial volume density without affecting fiber surface size (Chen et al, 2001). We set out to test whether organelles (ER, mitochondria) implicated in Ca 2ϩ homeostasis in PC somata and dendrites are affected by elimination of cytosolic Ca 2ϩ buffers.…”

Cytosolic Ca2+ Buffers

“…In the absence of PV in PV 2/2 mice, an up-regulation of mitochondria occurs not only in PV-ergic Purkinje cells (Chen et al 2006) or cerebellar stellate and basket cells (B Schwaller, unpubl. ), but is also seen in PV 2/2 fast-twitch muscle fibers (Chen et al 2001). The latter are characterized by high PV expression levels in WT mice.…”