Weight loss improves skeletal muscle mitochondrial energy efficiency

Abstract

Weight loss is associated with a disproportionate decrease in whole-body energy expenditure that may contribute to the heightened risk for weight-regain. Evidence suggests that this energetic mismatch originates from lean tissue. Although this phenomenon is well documented, the mechanisms have remained elusive. We hypothesized that increased mitochondrial energy efficiency in skeletal muscle is associated with reduced expenditure under weight loss. Wildtype male C57BL6/N mice were fed with high-fat diet for 10 wks, followed by a subset of mice that were maintained on the obesogenic diet (OB) or switched to standard chow to promote weight loss (WL) for additional 6 wks. Mitochondrial energy efficiency was evaluated using high-resolution respirometry and fluorometry. Mass spectrometric analyses were employed to describe the mitochondrial proteome and lipidome. Weight loss promoted ~50% increase in the efficiency of oxidative phosphorylation (ATP produced per O2consumed, or P/O) in skeletal muscle. However, weight loss did not appear to induce significant changes in mitochondrial proteome, nor any changes in respiratory supercomplex formation. Instead, it accelerated the remodeling of mitochondrial cardiolipin (CL) acyl-chains to increase tetralinoleoyl CL (TLCL) content, a species of lipids thought to be functionally critical for the respiratory enzymes. We further show that lowering TLCL by deleting the CL transacylase tafazzin was sufficient to reduce skeletal muscle P/O and protect mice from diet-induced weight gain. These findings implicate skeletal muscle mitochondrial efficiency as a novel mechanism by which weight loss reduces energy expenditure in obesity.

Partial skeletal muscle-specific Drp1 knockout enhances insulin sensitivity in diet-induced obese mice, but not in lean mice

“…Lastly, in regard to mitochondrial content, there were no significant changes in mitochondrial content in skeletal muscle from HFD-fed mice or primary myotubes derived from severely obese and insulin resistant humans as indicated by several protein markers. These results are consistent with several previous studies with the similar duration of HFD intervention or human muscle cell culture model [ [44] , [45] , [46] , [47] , [48] ], but conflict with a couple studies where either longer period of HFD intervention was applied or myotubes from T2D humans were studied [ 44 , 49 ]. Taken together, it suggests that mitochondrial content does not change until later in the development of insulin resistance and T2D.…”

Skeletal muscle PGC-1α remodels mitochondrial phospholipidome but does not alter energy efficiency for ATP synthesis

“…Prola et al demonstrated that reduced CL coincides with lower muscle P/O, and reconstitution of mitochondrial CL with unilamellar vesicles can restore P/O [30]. In our previous study, we demonstrated that weight loss also increases TLCL and CL transacylase tafazzin [27]. In that study, we also demonstrated that global tafazzin knockdown decreases muscle P/O and increases systemic metabolic rate.…”

“…PmFB were prepared as previously described [27]. Briefly, a small portion of freshly dissected red GAS muscle was placed in buffer X [7.23 mM K 2 EGTA, 2.77 mM Ca K 2 EGTA, 20 mM imidazole, 20 mM taurine, 5.7 mM ATP, 14.3 mM phosphocreatine, 6.56 mM MgCl 2 ·6H 2 O, and 50 mM 2-(N-Morpholino) ethanesulfonic acid potassium salt (K-MES) (pH7.4)].…”