title: Pharmacological enhancement of leg and muscle microvascular blood flow does not augment anabolic responses in skeletal muscle of young men under fed conditions.
abstract: Skeletal muscle anabolism associated with postprandial plasma aminoacidemia and insulinemia is contingent upon amino acids (AA) and insulin crossing the microcirculation-myocyte interface. In this study, we hypothesized that increasing muscle microvascular blood volume (flow) would enhance fed-state anabolic responses in muscle protein turnover. We studied 10 young men (23.2 ± 2.1 yr) under postabsorptive and fed [iv Glamin (∼10 g AA), glucose ∼7.5 mmol/l] conditions. Methacholine was infused into the femoral artery of one leg to determine, via bilateral comparison, the effects of feeding alone vs. feeding plus pharmacological vasodilation. We measured leg blood flow (LBF; femoral artery) by Doppler ultrasound, muscle microvascular blood volume (MBV) by contrast-enhanced ultrasound (CEUS), muscle protein synthesis (MPS) and breakdown (MPB; a-v balance modeling), and net protein balance (NPB) using [1,2-(13)C2]leucine and [(2)H5]phenylalanine tracers via gas chromatography-mass spectrometry (GC-MS). Indexes of anabolic signaling/endothelial activation (e.g., Akt/mTORC1/NOS) were assessed using immunoblotting techniques. Under fed conditions, LBF (+12 ± 5%, P < 0.05), MBV (+25 ± 10%, P < 0.05), and MPS (+129 ± 33%, P < 0.05) increased. Infusion of methacholine further enhanced LBF (+126 ± 12%, P < 0.05) and MBV (+79 ± 30%, P < 0.05). Despite these radically different blood flow conditions, neither increases in MPS in response to feeding (0.04 ± 0.004 vs. 0.08 ± 0.01%/h, P < 0.05) nor improvements in NPB (-4.4 ± 2.4 vs. 16.4 ± 5.7 nmol Phe·100 ml leg(-1)·min(-1), P < 0.05) were affected by methacholine infusion (MPS 0.07 ± 0.01%/h; NPB 24.0 ± 7.7 nmol Phe·100 ml leg(-1)·min(-1)), whereas MPB was unaltered by either feeding or infusion of methacholine. Thus, enhancing LBF/MBV above that occurring naturally with feeding alone does not improve muscle anabolism.
authors.affiliation: Division of Medical Science and Graduate Entry Medicine, University of Nottingham, Royal Derby Hospital, Derby, United Kingdom; and.
authors.forename: Bethan E
authors.initials: BE
authors.lastname: Phillips
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Atherton
authors.forename: Krishna
authors.initials: K
authors.lastname: Varadhan
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Wilkinson
authors.forename: Marie
authors.initials: M
authors.lastname: Limb
authors.forename: Anna L
authors.initials: AL
authors.lastname: Selby
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Rennie
authors.forename: Kenneth
authors.initials: K
authors.lastname: Smith
authors.forename: John P
authors.initials: JP
authors.lastname: Williams
mesh_terms: D000328:Adult; D000596:Amino Acids / Q000494:pharmacology; D001786:Blood Glucose / Q000032:analysis; D004435:Eating / Q000502:physiology*; D006801:Humans; D007866:Leg / Q000098:blood supply*; D008297:Male; D016210:Methacholine Chloride / Q000494:pharmacology*; D055806:Microvessels / Q000187:drug effects; D018482:Muscle, Skeletal / Q000098:blood supply / Q000187:drug effects* / Q000378:metabolism*; D010649:Phenylalanine / Q000097:blood; D012039:Regional Blood Flow / Q000187:drug effects*; D055815:Young Adult
chemical_list: D000596:Amino Acids; D001786:Blood Glucose; D016210:Methacholine Chloride; D010649:Phenylalanine
keywords: blood flow; muscle; protein metabolism