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, Gloria Bonuccelli, Carlo Minetti, Scott E. Woodman, Franco Capozza, Robert G. Kemp, Philipp E. Scherer, Michael P. Lisanti

Research output: Contribution to journalArticle

27 Citations (Scopus)

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 translocating 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 [ΔTFT (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.

Original languageEnglish (US)
Pages (from-to)2619-2634
Number of pages16
JournalAmerican Journal of Pathology
Volume163
Issue number6
StatePublished - Dec 2003

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Caveolin 3
Phosphofructokinases
Protein Isoforms
Cell Membrane
Muscles
Membranes
Distal Myopathies
Limb-Girdle Muscular Dystrophies
Caveolae
Mutation
Immunoprecipitation

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

Cite this

Phosphofructokinase Muscle-Specific Isoform Requires Caveolin-3 Expression for Plasma Membrane Recruitment and Caveolar Targeting : Implications for the Pathogenesis of Caveolin-Related Muscle Diseases. / Sotgia, Federica; Bonuccelli, Gloria; Minetti, Carlo; Woodman, Scott E.; Capozza, Franco; Kemp, Robert G.; Scherer, Philipp E.; Lisanti, Michael P.

In: American Journal of Pathology, Vol. 163, No. 6, 12.2003, p. 2619-2634.

Research output: Contribution to journalArticle

Sotgia, Federica ; Bonuccelli, Gloria ; Minetti, Carlo ; Woodman, Scott E. ; Capozza, Franco ; Kemp, Robert G. ; Scherer, Philipp E. ; Lisanti, Michael P. / Phosphofructokinase Muscle-Specific Isoform Requires Caveolin-3 Expression for Plasma Membrane Recruitment and Caveolar Targeting : Implications for the Pathogenesis of Caveolin-Related Muscle Diseases. In: American Journal of Pathology. 2003 ; Vol. 163, No. 6. pp. 2619-2634.
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