title: Inhibition of neutral sphingomyelinases in skeletal muscle attenuates fatty-acid induced defects in metabolism and stress.
abstract: BACKGROUND
  Chronic metabolic overload leads to insulin resistance in a variety of tissues. It has been shown that exposure to saturated fatty acid palmitate can cause insulin resistance in skeletal muscle cells. Fatty acid induced synthesis of ceramide is considered to be one of the major causes for insulin resistance. Both de novo synthesis and sphingomyelin hydrolysis by sphingomyelinase are implicated for ceramide generation. Aim of this study was to evaluate the impact of neutral sphingomyelinase (nSMase) inhibition on saturated fatty acid induced lipotoxicity and insulin resistance in skeletal muscle myotubes.
  
  
  RESULTS
  Treatment of saturated fatty acid (palmitate) but not unsaturated fatty acid (oleate) caused an up-regulation in expression of various nSMase genes which are associated with ceramide synthesis through the salvage pathway. Inhibition of nSMase by a pharmacological inhibitor (GW4869) partially reverted the palmitate induced insulin resistance in C2C12 myotubes. Inhibition of nSMase improved metabolic functions of myotubes as measured by improved oxidative capacity in terms of increased mitochondrial number, PGC1α expression and ATP levels with concomitant decrease in intramyocellular triglyceride levels. Palmitate induced inflammatory response was also reduced by nSMase inhibitor. GW4869 treatment reduced palmitate induced oxidative and endoplasmic reticulum stress and improved cell survival.
  
  
  CONCLUSIONS
  In this study, we provide evidences that inhibition of nSMase can protect skeletal muscles from saturated fatty acid induced insulin resistance, metabolic dysfunction, cellular stress and inflammation.
authors.affiliation: Connexios Life Sciences Private Ltd., No. 49, First Main road, 3rd phase, JP Nagar, Bangalore, 560 078 India.
authors.forename: Mahesh Kumar
authors.initials: MK
authors.lastname: Verma
authors.affiliation: Connexios Life Sciences Private Ltd., No. 49, First Main road, 3rd phase, JP Nagar, Bangalore, 560 078 India.
authors.forename: Aggunda Nagaraju
authors.initials: AN
authors.lastname: Yateesh
authors.affiliation: Connexios Life Sciences Private Ltd., No. 49, First Main road, 3rd phase, JP Nagar, Bangalore, 560 078 India.
authors.forename: Korrapati
authors.initials: K
authors.lastname: Neelima
authors.affiliation: Connexios Life Sciences Private Ltd., No. 49, First Main road, 3rd phase, JP Nagar, Bangalore, 560 078 India.
authors.forename: Niketa
authors.initials: N
authors.lastname: Pawar
authors.affiliation: Connexios Life Sciences Private Ltd., No. 49, First Main road, 3rd phase, JP Nagar, Bangalore, 560 078 India.
authors.forename: Kandoor
authors.initials: K
authors.lastname: Sandhya
authors.affiliation: Connexios Life Sciences Private Ltd., No. 49, First Main road, 3rd phase, JP Nagar, Bangalore, 560 078 India.
authors.forename: Jayaram
authors.initials: J
authors.lastname: Poornima
authors.affiliation: Connexios Life Sciences Private Ltd., No. 49, First Main road, 3rd phase, JP Nagar, Bangalore, 560 078 India.
authors.forename: Mudigere N
authors.initials: MN
authors.lastname: Lakshmi
authors.affiliation: Connexios Life Sciences Private Ltd., No. 49, First Main road, 3rd phase, JP Nagar, Bangalore, 560 078 India.
authors.forename: Sivakumaran
authors.initials: S
authors.lastname: Yogeshwari
authors.affiliation: Connexios Life Sciences Private Ltd., No. 49, First Main road, 3rd phase, JP Nagar, Bangalore, 560 078 India.
authors.forename: Puttrevana M
authors.initials: PM
authors.lastname: Pallavi
authors.affiliation: Connexios Life Sciences Private Ltd., No. 49, First Main road, 3rd phase, JP Nagar, Bangalore, 560 078 India.
authors.forename: Anup M
authors.initials: AM
authors.lastname: Oommen
authors.affiliation: Connexios Life Sciences Private Ltd., No. 49, First Main road, 3rd phase, JP Nagar, Bangalore, 560 078 India.
authors.forename: Baggavalli P
authors.initials: BP
authors.lastname: Somesh
authors.affiliation: Connexios Life Sciences Private Ltd., No. 49, First Main road, 3rd phase, JP Nagar, Bangalore, 560 078 India.
authors.forename: Madanahalli R
authors.initials: MR
authors.lastname: Jagannath
keywords: C2C12 myotubes; Cellular stress; Ceramide; Insulin resistance; Oxidative capacity; Sphingomyelinase; T2DM