Pyruvate kinase splice variants in fibroblasts influence cardiac remodeling after myocardial infarction in male mice

Fibroblasts are crucial for cardiac repair after myocardial infarction
(MI). In response to signaling cues, they differentiate to phenotypes with
robust capacities to synthesize and secrete extracellular matrix (ECM) and
signaling molecules. Although activated fibroblast phenotypes are
associated with pronounced changes in metabolism, it remains unclear how
the metabolic network upholds the effector functions of fibroblasts in the
infarcted heart.  We found that two enzymes that could facilitate
a phosphoenolpyruvate cycle, i.e. pyruvate kinase muscle isoform 2 (PKM2)
and phosphoenolpyruvate carboxykinase 2 (PCK2), are elevated in the heart
after MI. Although Pck2 deletion had no effect on post-MI remodeling,
fibroblast-specific switching of Pkm2 to Pkm1 (fbPkm2→1) mitigated
ventricular dilation, wall thinning, and losses in ejection fraction
caused by MI. Despite these salutary effects, fbPkm2→1 switching did not
alter cardiac fibrosis in vivo, nor did it affect collagen production,
cytokine or chemokine secretion, myofibroblast differentiation markers, or
transcriptional regulation in vitro. Nevertheless, Pkm2→1 splice variant
switching increased myofibroblast contractile activity as well as
influenced the metabolic phenotype of fibroblasts, as shown by increased
pyruvate kinase activity, higher mitochondrial respiratory capacity, and
elevation in glycolytic intermediate abundance. Despite these changes,
Pkm2→1 switching had relatively minor effects on glucose carbon fate, as
determined by stable isotope-resolved metabolomics. Nevertheless, these
metabolic data demonstrate that cardiac fibroblasts exhibit minimal
glucose-supported de novo glycine synthesis in vitro, yet possess high
hexosamine and glucuronate biosynthetic pathway activity. Collectively,
these findings reveal that fibroblast PKM isoforms influence post-MI
remodeling, highlighting pyruvate kinase as a potential therapeutic
target. This dataset includes a spreadsheet organized by figure number
that provides the raw data used for analysis in this study.