Mitochondrial Overload and Incomplete Fatty Acid Oxidation Contribute to Skeletal Muscle Insulin Resistance

Abstract

Previous studies have suggested that insulin resistance develops secondary to diminished fat oxidation and resultant accumulation of cytosolic lipid molecules that impair insulin signaling. Contrary to this model, the present study used targeted metabolomics to find that obesity-related insulin resistance in skeletal muscle is characterized by excessive beta-oxidation, impaired switching to carbohydrate substrate during the fasted-to-fed transition, and coincident depletion of organic acid intermediates of the tricarboxylic acid cycle. In cultured myotubes, lipid-induced insulin resistance was prevented by manipulations that restrict fatty acid uptake into mitochondria. These results were recapitulated in mice lacking malonyl-CoA decarboxylase (MCD), an enzyme that promotes mitochondrial beta-oxidation by relieving malonyl-CoA-mediated inhibition of carnitine palmitoyltransferase 1. Thus, mcd(-/-) mice exhibit reduced rates of fat catabolism and resist diet-induced glucose intolerance despite high intramuscular levels of long-chain acyl-CoAs. These findings reveal a strong connection between skeletal muscle insulin resistance and lipid-induced mitochondrial stress.

Metabolomic Profiling Identifies Novel Circulating Biomarkers of Mitochondrial Dysfunction Differentially Elevated in Heart Failure With Preserved Versus Reduced Ejection Fraction: Evidence for Shared Metabolic Impairments in Clinical Heart Failure

“…Importantly, these LCAC metabolites were significantly higher in HFrEF than HFpEF, inversely related to LVEF. As a reflection of impaired or dysregulated FAO, the elevated plasma LCAC observed may suggest a shared metabolic impairment of the HF clinical syndrome independent of LVEF 13, 53, 54. Given that FAO impairments or dysregulation may result from a variety of mitochondrial insults, further investigation will be needed to identify the causal processes underlying the LCAC elevations reported in this study 12, 83.…”

“…Functionally, they facilitate transfer of LCFAs into the mitochondria for ß‐oxidation 52. Although typically short‐lived, LCAC accumulate in states of inefficient fatty acid oxidation (FAO), which may be attributed to (1) defects in mitochondrial FAO enzymes or (2) increased FAO relative to tricarboxylic acid (TCA) flux; this leads to a bottleneck of carbon substrates at the TCA cycle 53, 54. Such defects can be caused or exacerbated by IR, which has, in turn, been associated with elevations in plasma LCAC 54, 55, 56, 57.…”

“…Although typically short‐lived, LCAC accumulate in states of inefficient fatty acid oxidation (FAO), which may be attributed to (1) defects in mitochondrial FAO enzymes or (2) increased FAO relative to tricarboxylic acid (TCA) flux; this leads to a bottleneck of carbon substrates at the TCA cycle 53, 54. Such defects can be caused or exacerbated by IR, which has, in turn, been associated with elevations in plasma LCAC 54, 55, 56, 57. However, we found no correlation between plasma LCAC and IR in this study; this suggests that the observed LCAC elevations were not driven by IR 54, 55, 56, 57.…”

“…Such defects can be caused or exacerbated by IR, which has, in turn, been associated with elevations in plasma LCAC 54, 55, 56, 57. However, we found no correlation between plasma LCAC and IR in this study; this suggests that the observed LCAC elevations were not driven by IR 54, 55, 56, 57. Regardless of the precise cause, LCAC are transported out to the plasma, where they are subsequently metabolized in several tissues (especially skeletal muscle, liver, and heart) or excreted in urine or bile 52, 56, 57.…”

Increased susceptibility to oxidative damage in post-diabetic human myotubes

“…However, the observation that lean, insulin-sensitive endurance-trained athletes have high levels of IMTG has led to the hypothesis that altered or incomplete lipid metabolism may be an important factor in the progression of insulin resistance (reviewed by van Loon and Goodpaster [9]). Along these lines, it has been proposed that the overflow of triacylglycerol metabolites in skeletal muscle mitochondria leads to an uncoupling of the tricarboxylic acid cycle and the electron transport chain (ETC), resulting in an accumulation of incompletely oxidised long-chain fatty acids [10]. These may thus be diverted from the tricarboxylic acid cycle into other lipid metabolites such as ceramides, diacylglycerol and/or acylcarnitines, which in turn can interfere with the insulin signalling pathway [10,11], as discussed in reviews [12][13][14].…”