Phosphofructokinase muscle-specific isoform requires caveolin-3 expression for plasma membrane recruitment and caveolar targeting: implications for the pathogenesis of caveolin-related muscle diseases.

Abstract

Previous co-immunoprecipitation studies have shown that endogenous PFK-M (phosphofructokinase, muscle-specific isoform) associates with caveolin (Cav)-3 under certain metabolic conditions. However, it remains unknown whether Cav-3 expression is required for the plasma membrane recruitment and caveolar targeting of PFK-M. Here, we demonstrate that recombinant expression of Cav-3 dramatically affects the subcellular localization of PFK-M, by targeting PFK-M to the plasma membrane, and by trans-locating PFK-M to caveolae-enriched membrane domains. In addition, we show that the membrane recruitment and caveolar targeting of PFK-M appears to be strictly dependent on the concentration of extracellular glucose. Interestingly, recombinant expression of PFK-M with three Cav-3 mutants [DeltaTFT (63 to 65), P104L, and R26Q], which harbor the same mutations as seen in the human patients with Cav-3-related muscle diseases, causes a substantial reduction in PFK-M expression levels, and impedes the membrane recruitment of PFK-M. Analysis of skeletal muscle tissue samples from Cav-3(-/-) mice directly demonstrates that Cav-3 expression regulates the phenotypic behavior of PFK-M. More specifically, in Cav-3-null mice, PFK-M is no longer targeted to the plasma membrane, and is excluded from caveolar membrane domains. As such, our current results may be important in understanding the pathogenesis of Cav-3-related muscle diseases, such as limb-girdle muscular dystrophy-1C, distal myopathy, and rippling muscle disease, that are caused by mutations within the human Cav-3 gene.

• Authors: Federica Sotgia, Gloria Bonuccelli, Carlo Minetti, Scott E Woodman, Franco Capozza, Robert G Kemp, Philipp E Scherer, Michael P Lisanti
• Journal: The American journal of pathology (Am J Pathol) Vol. 163 Issue 6 Pg. 2619-34 (Dec 2003) ISSN: 0002-9440 [Print] United States
• PMID: 14633633 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Cav1 protein, mouse
• Cav3 protein, mouse
• Caveolin 1
• Caveolin 3
• Caveolins
• Isoenzymes
• Recombinant Proteins
• Phosphofructokinases
• Glucose

Topics

• Animals
• COS Cells
• Caveolae (metabolism)
• Caveolin 1
• Caveolin 3
• Caveolins (deficiency, genetics, metabolism)
• Cell Line
• Cell Membrane (metabolism)
• Extracellular Fluid (metabolism)
• Glucose (metabolism)
• Isoenzymes (genetics, metabolism)
• Mice
• Mice, Knockout
• Muscle, Skeletal (enzymology, metabolism)
• Muscular Diseases (etiology)
• Mutation (physiology)
• Phenotype
• Phosphofructokinases (genetics, metabolism)
• Recombinant Proteins (metabolism)
• Tissue Distribution (physiology)