The transcriptional coactivator PGC-1α mediates exercise-induced angiogenesis in skeletal muscle

Abstract

Peripheral arterial disease (PAD) affects 5 million people in the US and is the primary cause of limb amputations. Exercise remains the single best intervention for PAD, in part thought to be mediated by increases in capillary density. How exercise triggers angiogenesis is not known. PPAR␥ coactivator (PGC)-1␣ is a potent transcriptional coactivator that regulates oxidative metabolism in a variety of tissues. We show here that PGC-1␣ mediates exercise-induced angiogenesis. Voluntary exercise induced robust angiogenesis in mouse skeletal muscle. Mice lacking PGC-1␣ in skeletal muscle failed to increase capillary density in response to exercise. Exercise strongly induced expression of PGC-1␣ from an alternate promoter. The induction of PGC-1␣ depended on ␤-adrenergic signaling. ␤-adrenergic stimulation also induced a broad program of angiogenic factors, including vascular endothelial growth factor (VEGF). This induction required PGC-1␣. The orphan nuclear receptor ERR␣ mediated the induction of VEGF by PGC-1␣, and mice lacking ERR␣ also failed to increase vascular density after exercise. These data demonstrate that ␤-adrenergic stimulation of a PGC-1␣/ERR␣/VEGF axis mediates exercise-induced angiogenesis in skeletal muscle.VEGF ͉ ERR␣ ͉ ␤-adrenergic

PGC-1α Mediated Muscle Aerobic Adaptations to Exercise, Heat and Cold Exposure

“…This is indeed unusual, as PGC-1α has been well shown to increase NRF1 expression and transcriptional activity (Wu et al, 1999) and consequently suggests other pathways besides PGC-1α might regulate NRF1 expression following post-exercise cold exposure. Regardless, this study lends some support for the study by Yamane et al (2006), as NRF1 has shown to encode a variety of mitochondrial components (Scarpulla, 2002) and PGC-1α has shown to act through ERRα in inducing VEGF expression (Chinsomboon et al, 2009). A key consideration however, that must be accounted for is that the increase in PGC-1α following cold exposure as demonstrated by Slivka et al (2013; was accompanied by significant elevations in whole body VO2 and shivering thermogenesis, which independently may increase PGC-1α mRNA expression.…”

“…Leick et al (2008) first showed that PGC-1α was not essential for exercise-induced mitochondrial biogenesis, where training-induced increases in COX1, Cyt c and δ-aminolevulinate synthase (ALAS) were not impaired in whole-body PGC-1α knock-out mice. Yet, whole-body PGC-1α deficiency is not an ideal model to study exercise-induced mitochondrial biogenesis in the skeletal muscle, as it is associated with numerous systemic effects, including hypermetabolism, hyperactivity and reluctance to exercise (Chinsomboon et al, 2009;Lin et al, 2004). Consequently, muscle specific PGC-1α knock-out models have been recently utilised in this line of research, but again with contradictory findings (Geng et al, 2010;Rowe et al, 2012;Uguccioni & Hood, 2011).…”

“…In addition, upregulation of VEGF mRNA following O2 depravation treatment (Arany et al, 2008) or β-adrenergic stimulation (Chinsomboon et al, 2009) has shown to be significantly lower in muscle cells derived from PGC-1α knock-out mice, compared with wild-type controls. The necessity of PGC-1α in VEGF mediated angiogenesis has also been demonstrated using exercise models, where capillary density was shown to be significantly increased in wild-type controls compared with PGC-1α muscle knock-out mice following 14 days of voluntary running (Chinsomboon et al, 2009). Collectively, these studies therefore indicate that in addition to regulating mitochondrial biogenesis, PGC-1α also has a role in angiogenic adaptations through its influence on VEGF.…”

Impact of cardiac rehabilitation and exercise training programs in coronary heart disease

“…69,70 Another mechanism is postulated to reflect angiogenesis in working muscles mediated by β-adrenergic stimulation of capillary growth by vascular endothelial growth factors and platelet-derived growth factors. 71 These processes are both stimulated by insulin-like-growth-factor-1, expressed proportionally with ET, and have been shown to reverse adrenergic related cardiac remodeling in animal models. 72 More recent studies have shown that ET-associated post-transcriptional gene regulation via micro-RNA reduces remodeling through interactions among metabolic, contractile and epigenetic genes.…”

Effect of exercise intensity and AICAR on isoform-specific expressions of murine skeletal muscle PGC-1α mRNA: a role of β2-adrenergic receptor activation

“…are three isoforms of PGC-1␣ mRNA, which promotes mitochondrial biogenesis and angiogenesis in skeletal muscles (6,25,46). Compared with PGC-1␣-a mRNA (a previously described isoform), PGC-1␣-b and PGC-1␣-c mRNAs are transcribed by a different exon 1 of the PGC-1␣ gene and produce slightly smaller-sized proteins.…”