Postexercise phosphocreatine recovery, an index of mitochondrial oxidative phosphorylation, is reduced in diabetic patients with lower extremity complications

Abstract

Objective To identify differences in the post-exercise phosphocreatine (PCr) recovery, an index of mitochondrial function, in diabetic patients with and without lower extremity complications. Research Methods and Design We enrolled healthy control subjects and three groups of T2DM patients: patients without complications, with peripheral neuropathy and both peripheral neuropathy and peripheral arterial disease. We employed Magnetic Resonance Spectroscopic (MRS) measurements to perform continuous measurements of phosphorous metabolites (PCr and Pi) during a 3-minute graded exercise at the level of the posterior calf muscles (gastrocnemius and soleus muscles). Micro- and macrovascular reactivity measurements were also performed. Results The resting Pi/PCr ratio and PCr at baseline and the maximum reached during exercise was similar in all groups. The post-exercise time required for recovery of Pi/PCr ratio and PCr levels to resting levels, an assessment of mitochondrial oxidative phosphorylation, was significantly higher in the diabetic patients with neuropathy and those with both neuropathy and PAD (p <0.01 for both measurements). These two groups had also higher levels of TNFα, (p<0.01) and G-CSF (p <0.05). Multiple regression analysis showed that only G-CSF, OPG and TNFα were significant contributing factors in the variation of the Pi/PCr ratio recovery time. No associations were observed between micro- and macrovascular reactivity measurements and Pi/Pcr ration or Pcr recovery time. Conclusions Mitochondrial oxidative phosphorylation is impaired only in T2DM patients with neuropathy whether PAD is present or not and is associated with the increased proinflammatory state that was observed in these groups.

Revascularization and muscle adaptation to limb demand ischemia in diet-induced obese mice

“…There was, however, a significant increase in muscle G-CSF protein content in the muscle with demand ischemia (Figure 3C) and this was associated with enhanced capillary density in the muscle with demand ischemia (Figure 1). Higher serum G-CSF levels were measured in diabetic PAD patients compared to controls or diabetics without comorbidities [12]. G-CSF receptors are expressed on a wide range of cell types including hematopoietic stem cells, myocytes and endothelial cells [30].…”

“…This finding may have functional implication as studies implied that increased circulating TNFα levels and enhanced TNFα expression by peripheral monocytes were associated with walking impairment in PAD patients with intermittent claudication [31]. Elevated circulating TNFα and a decrease in VEGF protein levels were also reported in diabetic PAD patients after exercise [11, 12]. TNFα is central to obesity-induced insulin resistance, and it has been implicated in skeletal muscle wasting associated with several pathological conditions [32].…”

Declining Skeletal Muscle Function in Diabetic Peripheral Neuropathy

“…71,72 Muscle oxidative capacity is reduced by over 50% in DPN compared to DM without neuropathy. 73 The reduced mitochondrial function in DPN is related to increased inflammatory cytokines. 73 A reduction in oxidative enzymes and mitochondria content has also been reported in striated muscle of DM (see Review).…”

“…73 The reduced mitochondrial function in DPN is related to increased inflammatory cytokines. 73 A reduction in oxidative enzymes and mitochondria content has also been reported in striated muscle of DM (see Review). 74 Declines in oxidative capacity are also reflected in slower rates of oxygen consumption during exercise in DM.…”

“…This impairment in oxidative capacity was approximately 50% in DPN compared to DM without neuropathy and was not affected by the presence of peripheral arterial disease. 73 …”