Introduction: Mitochondrial dysfunction is implicated in the metabolic myopathy accompanying peripheral artery disease (PAD) and critical limb ischemia (CLI). Type-2 diabetes mellitus (T2DM) is a major risk factor for PAD development and progression to CLI and may also independently be related to mitochondrial dysfunction. We set out to determine the effect of T2DM in the relationship between CLI and muscle mitochondrial respiratory capacity and coupling control. Methods: We studied CLI patients undergoing revascularization procedures or amputation, and non-CLI patients with or without T2DM of similar age. Mitochondrial respiratory capacity and function were determined in lower limb permeabilized myofibers by high-resolution respirometry. Results: Fourteen CLI patients (65 ± 10y) were stratified into CLI patients with (n = 8) or without (n = 6) T2DM and were compared to non-CLI patients with (n = 18; 69 ± 5y) or without (n = 19; 71 ± 6y) T2DM. Presence of CLI but not T2DM had a marked impact on all mitochondrial respiratory states in skeletal muscle, adjusted for the effects of sex. Leak respiration (State 2, P < 0.025 and State 4o, P < 0.01), phosphorylating respiration (P < 0.001), and maximal respiration in the uncoupled state (P < 0.001), were all suppressed in CLI patients, independent of T2DM. T2DM had no significant effect on mitochondrial respiratory capacity and function in adults without CLI. Conclusions: Skeletal muscle mitochondrial respiratory capacity was blunted by ∼35% in patients with CLI. T2DM was not associated with muscle oxidative capacity and did not moderate the relationship between muscle mitochondrial respiratory capacity and CLI.
|Number of pages||10|
|Journal||Journal of Surgical Research|
|State||Published - Aug 2023|
Bibliographical noteFunding Information:
Seed funding from the Department of Surgery, UTMB. This work was also supported by the following grants: NIH : T32 GM008256 , RO1 AG-033761 , RO1 AR-049877 , R56 AG05126701 , P30 AG024832 , and F30 AG058381 ; SHC-84080 ; and was conducted with the support of the Institute for Translational Sciences at UTMB , supported in part by a Clinical and Translational Science Award ( UL1TR000071 ).
- Critical limb ischemia
- Oxidative phosphorylation
- Peripheral artery disease
ASJC Scopus subject areas