Gene-Pharmacologial Effects on Exercise-Induced Muscle Gene Expression in Healthy Men

Abstract

Angiotensin 2 is a major vasoconstrictor and subject to complex regulation. It is produced by the angiotensinconverting enzyme (ACE), which is itself regulated by blood flow and represents a target for pharmacological (lisinopril) and genetical (ACE-I/D polymorphism) influences. 32 healthy Caucasian men of British descent, including six subjects that were treated with lisinopril, completed standardized one-legged cycling-type endurance exercise to assess ACE-I/D and lisinopril dependent levels alterations of ACE and hypoxia-modulated transcripts in knee extensor muscle. Lisinopril treatment revealed significantly decreased transcript expression at baseline (COX4I1 -88%; COX4I2 -67%; HIF-1α -93%) and 3 hours into recovery (HIF-1α -78%; ACE -62%). Furthermore, during recovery from cycling-type endurance exercise, COX4I2 mRNA expression was increased by 281% in ACE-II genotypes (p <0.05) but not in subjects carrying the ACE D-allele. Additionally, ACE-DD genotypes showed a trend for superior expression of ACE mRNA (p =0.07), whereas for carriers of the ACE I-allele a decrease (ACE-ID -35%; ACE-II -67%) was observed. Changes in COX4I2 and ACE transcript expression were correlated to HIF-1α protein levels prior to exercise, which was highest in ACE-DD genotypes. The interpretative hypothesis is suggested that exercise-induced COX4I2 transcript expression is sensitized in dependence of the I-allele, which silences ACE expression. The findings implicate a pronounced influence of anti-hypertensive treatment on muscle gene expression, which is modified by the ACE-I/D genotype. The observed effects of lisinopril and the ACE I-allele suggests a possible role of shear stress and tissue oxygenation on the expression of oxygen-associated transcripts during recovery from the sympatholytic challenge of endurance exercise. Gene-Pharmacologial Effects on Exercise-Induced Muscle Gene Expression in Healthy Men

Cellular Aspects of Muscle Specialization Demonstrate Genotype – Phenotype Interaction Effects in Athletes

“…In this respect, it is important to consider that in moderately trained subjects both the rs1799752 (and rs2104772) gene polymorphisms are associated with a different expression response of angiogenic processes as well as those of mitochondrial processes and amino acid metabolism in m. vastus lateralis subsequent to a single bout of endurance exercise (Vaughan et al, 2013, 2016; Valdivieso et al, 2017a,b). Collectively, the findings hint for a quantitative relevance of ACE-related genetic influences on the exercise-specific expression responses of skeletal muscle (Flueck, 2009; Vaughan et al, 2013; Mathes et al, 2015) which remains to be addressed.…”

“…Consistently, ACE I-allele carriers are found to demonstrate greater increases in the volume density of subsarcolemmal mitochondria, and intramyocellular lipid stores in m. vastus lateralis after endurance training (Vaughan et al, 2013). The relevance of the ACE-related response of m. vastus lateralis to endurance exercise, and the contribution of its genetic inhibition via the ACE I-allele, is corroborated by the effects of pharmacological ACE inhibition on metabolism-related transcript in m. vastus lateralis post endurance exercise and training (Zoll et al, 2006; van Ginkel et al, 2016), and the fact that this shift in transcript expression is modulated by the ACE-I/D gene polymorphism (Mathes et al, 2015). For instance, oral intake of the ACE inhibitor lisinopril increased transcript levels of the shear stress-related pro-angiogenic factors VEGF and tenascin-C in m. vastus lateralis when the levels of hypoxia-related mitochondrial transcripts were lowered (van Ginkel et al, 2015).…”

“…Specifically the I-allele represented by polymorphism rs1799752, which characterizes the insertion of a silencer region within intron 16 of the ACE gene, is found to be associated with superior trainability of endurance performance compared to subject being characterized by the homozygous deletion of the silencer region (i.e., ACE-D/D genotypes; (Woods et al, 2000; Flueck et al, 2010). ACE I-allele carriers (i.e., ACE-I/I and ACE-I/D genotypes) have been found to demonstrate lower ACE transcript expression in skeletal muscle, and reduced serum levels of the encoded ACE, and its product, the major vasoconstrictor angiotensin 2, than ACE-D/D genotypes (Rigat et al, 1990; Vaughan et al, 2013; Mathes et al, 2015; Vaughan et al, 2016). Consequently ACE-I/I and ACE-I/D genotypes show increased capillary perfusion during exhaustive endurance exercise when capillary perfusion is not improved in ACE-D/D genotypes (van Ginkel et al, 2015).…”

“…Consequently ACE-I/I and ACE-I/D genotypes show increased capillary perfusion during exhaustive endurance exercise when capillary perfusion is not improved in ACE-D/D genotypes (van Ginkel et al, 2015). The reportedly reduced improvement of blood supply in ACE-D/D compared to ACE-I/I and I/D genotypes is related to an inefficient import of serum glucose, perturbed mitochondrial metabolism (Vaughan et al, 2016), and lower transcript expression of lipid and glucose metabolism-associated factors in knee extensor muscle of ACE-D/D genotypes at the end of exhaustive endurance exercise (Mathes et al, 2015). Consistently, ACE I-allele carriers are found to demonstrate greater increases in the volume density of subsarcolemmal mitochondria, and intramyocellular lipid stores in m. vastus lateralis after endurance training (Vaughan et al, 2013).…”