Perlecan regulates exercise-induced PGC-1α isoform expression and angiogenic gene program in skeletal muscle

Exercise induces diverse adaptations in skeletal muscle, and extracellular matrix remodeling plays a key role in these adaptations. Capillaries, which are essential for transporting oxygen and other molecules to maintain skeletal muscle function, are crucial for exercise adaptation. Perlecan, a heparan sulfate proteoglycan and a major basement membrane molecule in skeletal muscle, has been implicated in capillary formation and maintenance. However, its role in exercise adaptation remains unclear. Herein, we used male mice lacking perlecan expression outside of cartilage (Hspg2^-/--Tg) as well as Hspg2 wild-type transgenic control mice to examine the regulatory relationship between perlecan and PGC-1α isoforms, which are key mediators of exercise-induced metabolic and angiogenic responses. Following acute treadmill exercise, Hspg2^-/--Tg mice showed a significant increase in the mRNA expression of alternative promoter-driven PGC-1α isoforms (ex1b and ex1b') 3 h after exercise, whereas proximal promoter-driven isoforms showed little response. This isoform-specific response was accompanied by enhanced expression of angiogenesis-related genes, including Vegfa, Angpt1, Angpt2, and Hif1a, which peaked 3 h after exercise in perlecan-deficient muscle. In parallel with these transcriptional changes, immunofluorescent analysis revealed significantly higher baseline capillary density in Hspg2^-/--Tg quadriceps muscle, a difference that became even more pronounced after 2 wk of exercise training. These findings demonstrate that perlecan deficiency enhances baseline vascular remodeling features and the angiogenic transcriptional response to exercise, suggesting that the composition of the basement membrane extracellular matrix critically regulates exercise-induced PGC-1α isoform expression and muscle-vascular crosstalk during skeletal muscle adaptation.