Palmitate-induced changes in energy demand cause reallocation of ATP supply in rat and human skeletal muscle cells

TY - JOUR

T1 - Palmitate-induced changes in energy demand cause reallocation of ATP supply in rat and human skeletal muscle cells

AU - Nisr, Raid B.

AU - Affourtit, Charles

N1 - Funding Information: This work was supported by the Medical Research Council [New Investigator Research Grant G1100165 to CA] and Plymouth University [salary support for RBN]. Neither MRC nor Plymouth University were involved in the design and execution of this study, the analysis and interpretation of the data, or in the writing of the manuscript. It was the decision of the authors only to submit the manuscript for publication. We thank Prof. Andrew Jones and Mr. Lee Wiley (Sport and Health Sciences, College of Life and Environmental Sciences, University of Exeter) for taking the human skeletal muscle biopsies, Prof. Paul Winyard (Exeter University Medical School, UK) for providing licenced facilities to work with human tissue, and Dr Jane Carré (Plymouth University, UK) for help with the human muscle cell isolation. Copyright: © 2016 Elsevier B.V. All rights reserved.

PY - 2016/9/1

Y1 - 2016/9/1

N2 - Mitochondrial dysfunction has been associated with obesity-related muscle insulin resistance, but the causality of this association is controversial. The notion that mitochondrial oxidative capacity may be insufficient to deal appropriately with excessive nutrient loads is for example disputed. Effective mitochondrial capacity is indirectly, but largely determined by ATP-consuming processes because skeletal muscle energy metabolism is mostly controlled by ATP demand. Probing the bioenergetics of rat and human myoblasts in real time we show here that the saturated fatty acid palmitate lowers the rate and coupling efficiency of oxidative phosphorylation under conditions it causes insulin resistance. Stearate affects the bioenergetic parameters similarly, whereas oleate and linoleate tend to decrease the rate but not the efficiency of ATP synthesis. Importantly, we reveal that palmitate influences how oxidative ATP supply is used to fuel ATP-consuming processes. Direct measurement of newly made protein demonstrates that palmitate lowers the rate of de novo protein synthesis by more than 30%. The anticipated decrease of energy demand linked to protein synthesis is confirmed by attenuated cycloheximide-sensitivity of mitochondrial respiratory activity used to make ATP. This indirect measure of ATP turnover indicates that palmitate lowers ATP supply reserved for protein synthesis by at least 40%. This decrease is also provoked by stearate, oleate and linoleate, albeit to a lesser extent. Moreover, palmitate lowers ATP supply for sodium pump activity by 60-70% and, in human cells, decreases ATP supply for DNA/RNA synthesis by almost three-quarters. These novel fatty acid effects on energy expenditure inform the 'mitochondrial insufficiency' debate.

AB - Mitochondrial dysfunction has been associated with obesity-related muscle insulin resistance, but the causality of this association is controversial. The notion that mitochondrial oxidative capacity may be insufficient to deal appropriately with excessive nutrient loads is for example disputed. Effective mitochondrial capacity is indirectly, but largely determined by ATP-consuming processes because skeletal muscle energy metabolism is mostly controlled by ATP demand. Probing the bioenergetics of rat and human myoblasts in real time we show here that the saturated fatty acid palmitate lowers the rate and coupling efficiency of oxidative phosphorylation under conditions it causes insulin resistance. Stearate affects the bioenergetic parameters similarly, whereas oleate and linoleate tend to decrease the rate but not the efficiency of ATP synthesis. Importantly, we reveal that palmitate influences how oxidative ATP supply is used to fuel ATP-consuming processes. Direct measurement of newly made protein demonstrates that palmitate lowers the rate of de novo protein synthesis by more than 30%. The anticipated decrease of energy demand linked to protein synthesis is confirmed by attenuated cycloheximide-sensitivity of mitochondrial respiratory activity used to make ATP. This indirect measure of ATP turnover indicates that palmitate lowers ATP supply reserved for protein synthesis by at least 40%. This decrease is also provoked by stearate, oleate and linoleate, albeit to a lesser extent. Moreover, palmitate lowers ATP supply for sodium pump activity by 60-70% and, in human cells, decreases ATP supply for DNA/RNA synthesis by almost three-quarters. These novel fatty acid effects on energy expenditure inform the 'mitochondrial insufficiency' debate.

KW - ATP turnover

KW - Mitochondrial dysfunction

KW - Obesity

KW - Palmitate-induced insulin resistance

KW - Skeletal muscle

KW - Type 2 diabetes

UR - https://www.scopus.com/pages/publications/84973467511

U2 - 10.1016/j.bbabio.2016.04.286

DO - 10.1016/j.bbabio.2016.04.286

M3 - Article

C2 - 27154056

AN - SCOPUS:84973467511

SN - 0005-2728

VL - 1857

SP - 1403

EP - 1411

JO - Biochimica et Biophysica Acta - Bioenergetics

JF - Biochimica et Biophysica Acta - Bioenergetics

IS - 9

ER -