Muscle oxygenation and ATP turnover when blood flow is impaired by vascular disease

Abstract

In exercising muscle, creatine kinase ensures that mismatch between ATP supply and ATP use results in net phosphocreatine (PCr) splitting. This,inter alia, makes31P magnetic resonance spectroscopy a useful tool for studying muscle ‘energy metabolism’ noninvasivelyin vivo. We combined this with near–infrared spectroscopy (NIRS) to study ATP synthesis and oxygenation in calf muscle of normal subjects and patients with peripheral vascular disease. Experimental and clinical details and basic data have been published elsewhere (G.J. Kemp et al.,Journal of Vascular Surgery34 (2001), 1103–10); we here propose an analysis of interactions between metabolic ‘error signals’ and cellular PO2(estimated from NIRS changes, provisionally assumed to reflect deoxymyoglobin). Post–exercise PCr recovery is monoexponential, and the linear relationship between PCr resynthesis rate (= oxidative ATP synthesis) and the perturbation in PCr (conceptually the simplest error signal) is consistent with negative feedback. In patients the inferred ‘mitochondrial capacity’ (= oxidative ATP synthesis at ‘zero’ PCr) is decreased by 53±6%, leading to reduced oxidative ATP contribution in exercise, because of increased deoxygenation. Increased PCr perturbation partially outweighs cellular hypoxia, but as low cellular PO2is required for capillary–mitochondrion O2diffusion, rate–signal relationships may overstate maximum oxidative ATP synthesis rate.

Skeletal muscle StO2 kinetics are slowed during low work rate calf exercise in peripheral arterial disease

“…*P < 0.05, PAD vs. Control is also shown similar in PAD and control subjects during low work rate exercise, yet the time course of muscle oxygen desaturation was prolonged in PAD muscle. Given the apparent similarities in blood flow responses during low work rates, the slower rate of desaturation is most consistent with a slower dynamic increase of muscle oxygen consumption in the PAD-affected muscle (Ferreira et al 2005), a finding that is consistent with the abnormalities of oxidative metabolism previously reported in PAD subjects (Brass et al 2001;Kemp et al 2002;Pipinos et al 2003Pipinos et al , 2006. For example, specific enzymes of the electron transport chain exhibit decreased activities on a per mitochondrion basis in muscle from PAD patients (Brass et al 2001).…”

“…Thirty second CBF data are from four PAD and four controls assessed following independent exercise trials lasting 30 s. All other data represent mean ± SE of eight subjects per group. *P < 0.05, **P < 0.01 PAD vs. control reliance upon non-oxidative means of ATP synthesis early in exercise (Kemp et al 2002). The accumulation of metabolites (e.g.…”

“…For example, specific enzymes of the electron transport chain exhibit decreased activities on a per mitochondrion basis in muscle from PAD patients (Brass et al 2001). Moreover, in vivo data indicate the initial rate of oxidative ATP synthesis following the onset of exercise is reduced in PAD skeletal muscle, suggesting a role for abnormal control of oxidative metabolism in the muscle of subjects with PAD (Kemp et al 2002). Damage to skeletal muscle mitochondria and potential impairment of function is consistent with the finding of mitochondrial ischemia-reperfusion injury observed in other models such as myocardium (Lesnefsky and Hoppel 2003).…”

Short-term treatment with a novel HIF-prolyl hydroxylase inhibitor (GSK1278863) failed to improve measures of performance in subjects with claudication-limited peripheral artery disease

“…26 Changes in mitochondrial respiration, microcirculatory function and structure, skeletal muscle organization, nerve-muscle interface, and muscle metabolic function also significantly contribute to the disease pathophysiology. [26][27][28][29][30][31][32] Accordingly, the hypothesis tested in the present study was predicated on evidence, demonstrating the ability of GSK1278863 to induce HIF-responsive mechanisms, such as EPO and HIF target gene mRNA induction within hours of administration, and suggesting that acute exercise and IPC can induce HIF-responsiveness. 33,34 Although both regimens of GSK1278863 studied were adequate to engage the PHD pathway, no symptomatic or performance benefit ensued.…”

Dynamic phosphocreatine imaging with unlocalized pH assessment of the human lower leg muscle following exercise at 3T

“…Applying a mask from 1 H images, we calculated the total time‐resolved PCr signal from the VOI (i.e., the gastrocnemius muscle) and subtracted the estimated noise contribution based on the average signal noise outside the leg. The PCr recovery curve after exercise was normalized to the value at rest (by averaging the last five time points of the curve) and fitted to a monoexponential model : , resulting in three fitting parameters: normalized PCr signal at the end of exercise ( PCr 0 ), normalized PCr depletion ( ΔPCr ), and τ PCr (in seconds). After PCr excitation and acquisition, we implemented a second frequency selective pulse to acquire unlocalized spectra of Pi within the same TR, which allowed us to extract pH information in the muscle (Fig.…”