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(American Journal of Pathology. 2003;163:2619-2634.)
© 2003 American Society for Investigative Pathology

Animal Model

Phosphofructokinase Muscle-Specific Isoform Requires Caveolin-3 Expression for Plasma Membrane Recruitment and Caveolar Targeting

Implications for the Pathogenesis of Caveolin-Related Muscle Diseases

Federica Sotgia*{dagger}, Gloria Bonuccelli*{dagger}, Carlo Minetti{dagger}, Scott E. Woodman*, Franco Capozza*, Robert G. Kemp{ddagger}, Philipp E. Scherer§ and Michael P. Lisanti*

From the Departments of Molecular Pharmacology* and Cell Biology,§ and The Albert Einstein Cancer Center, Albert Einstein College of Medicine, Bronx, New York; the Department of Biochemistry and Molecular Biology,{ddagger} The Chicago Medical School, North Chicago, Illinois; and the Servizio Malattie Neuro-Muscolari,{dagger} Università di Genova, Istituto Gaslini, Genova, Italy

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 [{Delta}TFT (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.




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