Skeletal Muscle Proteomic Profile Revealed Gender-Related Metabolic Responses in a Diet-Induced Obesity Animal Model

Abstract

Obesity is a chronic, complex pathology associated with a risk of developing secondary pathologies, including cardiovascular diseases, cancer, type 2 diabetes (T2DM) and musculoskeletal disorders. Since skeletal muscle accounts for more than 70% of total glucose disposal, metabolic alterations are strictly associated with the onset of insulin resistance and T2DM. The present study relies on the proteomic analysis of gastrocnemius muscle from 15 male and 15 female C56BL/J mice fed for 14 weeks with standard, 45% or 60% high-fat diets (HFD) adopting a label-free LC–MS/MS approach followed by bioinformatic pathway analysis. Results indicate changes in males due to HFD, with increased muscular stiffness (Col1a1, Col1a2, Actb), fiber-type switch from slow/oxidative to fast/glycolytic (decreased Myh7, Myl2, Myl3 and increased Myh2, Mylpf, Mybpc2, Myl1), increased oxidative stress and mitochondrial dysfunction (decreased respiratory chain complex I and V and increased complex III subunits). At variance, females show few alterations and activation of compensatory mechanisms to counteract the increase of fatty acids. Bioinformatics analysis allows identifying upstream molecules involved in regulating pathways identified at variance in our analysis (Ppargc1a, Pparg, Cpt1b, Clpp, Tp53, Kdm5a, Hif1a). These findings underline the presence of a gender-specific response to be considered when approaching obesity and related comorbidities.

Brain sex-dependent alterations after prolonged high fat diet exposure in mice

“…In line with our findings, in a large study on obese subjects, gray matter density of different brain regions, including bilateral frontal lobes and cerebellum, was associated with BMI in males but not in females 40 . Despite the milder peripheral metabolic response of females, which was demonstrated also in the skeletal muscle of the same animal model after 14 weeks of HFD 41 , ACX transcriptomic analysis revealed in both sexes, a prominent HFD-induced downregulation of gene transcripts associated with nervous system development, axonal guidance, synaptic transmission, regulation of protein misfolding and BBB integrity, confirming previous evidence 42,43 . The down-regulation of excitatory synapse organizer Cerebellin1 40 observed only in males fed with 60HFD, may help explain the significant reduction of excitatory synapse receptor proteins observed in males.…”

“…A separate group of 30 mice were sacrificed at the end of 14 weeks and dedicated to liver immunohistochemistry and serum analyses. The same group was part of a study already published on HFD induced muscle damage 41 .…”

Sex-specific changes in metabolism during the transition from chow to high-fat diet feeding are abolished in response to dieting in C57BL/6J mice

“…The protection against obesity in female mice has been attributed to the effects of circulating oestrogen levels on glucose and insulin homoeostasis, body fat distribution, pro-inflammatory markers, and hepatic lipogenesis [ 26 – 29 ]. Ovariectomy has been shown to eliminate the protection of female mice to gaining weight on a HFD [ 30 ].…”

Ubiquitin-Specific Proteases (USPs) and Metabolic Disorders

“…Fast fibers, such as myosin heavy chain (Myh) IIB and IIX-positive fibers, preferably obtain ATP by glycolysis, while slow fibers, such as Myh I and IIA-positive fibers produce ATP by oxidative phosphorylation in mitochondria [ 82 ]. Since slow fibers consume more carbohydrates than fast fibers, conversion of fast to slow fibers prevents obesity and subsequent T2DM onset [ 83 ]…”