The impact of exercise on insulin sensitivity, mitochondrial dynamics and oxidative capacity

Background Decreased oxidative phosphorylation capacity and mitochondrial contents as well as altered mitochondrial dynamics in skeletal muscle (SkM) characterizes people with insulin resistance and type 2 diabetes mellitus.

Hypothesis Exercise training alters mitochondrial dynamics towards a more fused mitochondrial network, which results in enhanced SkM oxidative phosphorylation capacity and improved insulin sensitivity.

Methods We employed simulated exercising in murine C2C12 myoblasts using electrical pulse stimulation (EPS) for 24 hours, which was validated by release of interleukin-6 (IL-6), as measured using enzyme-linked immunosorbent assay. Palmitate treatment (PAL) for 24 hours was performed to mimic lipid-induced insulin resistance. Using Western blotting, insulin sensitivity was assessed from insulin-stimulated serine/threonine phosphorylation of AKT at S473 and T308, respectively, while lipid-induced insulin resistance was assessed from serine phosphorylation of insulin receptor substrate 1 (IRS1) at S1101. Furthermore, we measured protein expression of markers reflecting mitochondrial dynamics (pDRP1, DRP1, MFN1, MFN2, OPA1). Oxidative phosphorylation capacity was quantified by high-resolution respirometry and corrected for mitochondrial content, which as assessed from citrate synthase activity. We compared four experimental groups: (i) control (CON), (ii) EPS, (iIi) PAL and (iv) combined EPS+PAL to examine the combined effect of exercising and palmitate on insulin signalling.

Results EPS did not affect insulin signaling, while PAL decreased AKT phosphorylation at S473 and T308 by 41 an 54%, respectively, compared to CON (p=0.0015 and p=0.0044). EPS+PAL led to a 19% and 17% lower decrease of AKT-phosphorylation at S473 and T308, respectively, than PAL alone (p). Serine phosphorylation of IRS1 did not differ between the groups. Of note, mitochondrial proton leakage was 38% and 64% higher in PAL and EPS+PAL, respectively, than in CON (p). The maximal oxidative phosphorylation capacity, expression of markers of mitochondrial dynamics and mitochondrial content were not different between the groups.

Conclusions In myotubes, palmitate induces insulin resistance by interfering with distal, but not with proximal insulin signaling. The 24-h EPS protocol, which resembles characteristics of in vivo exercising, partly reverses lipid-induced insulin resistance. This effect is largely independent of mitochondrial function and mass. These data indicate that exercising may help to improve, but cannot reverse lipid-induced muscle insulin resistance.

Interessenkonflikt

Michael Roden received personal fees from Allergan, Astra-Zeneca, Boehringer-Ingelheim, Echosens, Eli Lilly, Gilead Sciences, Madrigal, Novo Nordisk, Pfizer and investigator-initiated research support from Boehringer-Ingelheim, Nutricia/Danone and Sanofi-Aventis.

Publication History

Article published online:
18 April 2024