Aberrant lipid metabolism promotes the development of skeletal muscle insulin resistance, but the exact identity of lipid-mediated mechanisms relevant to human obesity remains unclear. A comprehensive lipidomic analysis of primary myocytes from individuals that are insulin-sensitive and lean (LN) or insulin-resistant with obesity (OB) revealed several species of lysophospholipids (lyso-PL) that were differentially-abundant. These changes coincided with greater expression of lysophosphatidylcholine acyltransferase 3 (LPCAT3), an enzyme involved in phospholipid transacylation (Lands cycle). Strikingly, mice with skeletal muscle-specific knockout of LPCAT3 (LPCAT3-MKO) exhibited greater muscle lyso-PC/PC, concomitant with improved skeletal muscle insulin sensitivity. Conversely, skeletal muscle-specific overexpression of LPCAT3 (LPCAT3-MKI) promoted glucose intolerance. The absence of LPCAT3 reduced phospholipid packing of cellular membranes and increased plasma membrane lipid clustering, suggesting that LPCAT3 affects insulin receptor phosphorylation by modulating plasma membrane lipid organization. In conclusion, obesity accelerates the skeletal muscle Lands cycle, whose consequence might induce the disruption of plasma membrane organization that suppresses muscle insulin action.

41Exercise capacity is a strong predictor of all-cause mortality. Skeletal muscle mitochondrial 42 respiratory capacity, its biggest contributor, adapts robustly to changes in energy demands 43 induced by contractile activity. While transcriptional regulation of mitochondrial enzymes has 44 been extensively studied, there is limited information on how mitochondrial membrane lipids are 45 regulated. Herein, we show that exercise training or muscle disuse alters mitochondrial 46 membrane phospholipids including phosphatidylethanolamine (PE). Addition of PE promoted, 47 whereas removal of PE diminished, mitochondrial respiratory capacity. Surprisingly, skeletal 48 muscle-specific inhibition of mitochondrial-autonomous synthesis of PE caused a respiratory 49 failure due to metabolic insults in the diaphragm muscle. While mitochondrial PE deficiency 50 coincided with increased oxidative stress, neutralization of the latter did not rescue lethality. 51 These findings highlight the previously underappreciated role of mitochondrial membrane 52 phospholipids in dynamically controlling skeletal muscle energetics and function. 53 54 55 157 3B&C), without changes in abundance of ETS enzymes (Figure 3D). PE molecules are bound to 158 ETS complexes I, II, III, and IV, likely facilitating conformational changes and acting as an 159

Exercise capacity is a strong predictor of all-cause mortality. Skeletal muscle mitochondrial respiratory capacity, its biggest contributor, adapts robustly to changes in energy demands induced by contractile activity. While transcriptional regulation of mitochondrial enzymes has been extensively studied, there is limited information on how mitochondrial membrane lipids are regulated. Here, we show that exercise training or muscle disuse alters mitochondrial membrane phospholipids including phosphatidylethanolamine (PE). Addition of PE promoted, whereas removal of PE diminished, mitochondrial respiratory capacity. Unexpectedly, skeletal muscle–specific inhibition of mitochondria-autonomous synthesis of PE caused respiratory failure because of metabolic insults in the diaphragm muscle. While mitochondrial PE deficiency coincided with increased oxidative stress, neutralization of the latter did not rescue lethality. These findings highlight the previously underappreciated role of mitochondrial membrane phospholipids in dynamically controlling skeletal muscle energetics and function.

The biophysical environment of membrane phospholipids affects structure, function, and stability of membrane-bound proteins. 1,2 Obesity can disrupt membrane lipids, and in particular, alter the activity of sarco/endoplasmic reticulum (ER/SR) Ca 2+ -ATPase (SERCA) to affect cellular Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:

The premise of this study was to examine the efficacy of genetic suppression of mitochondrial reactive oxygen species (ROS) to attenuate disuse-induced muscle atrophy and muscle weakness. Neutralization of mitochondrial ROS by MCAT expression was insufficient to rescue muscle atrophy and muscle weakness.