Accumulation of Advanced Glycation End-Products and Activation of the SCAP/SREBP Lipogenetic Pathway Occur in Diet-Induced Obese Mouse Skeletal Muscle

Abstract

Aim of this study was to investigate whether advanced glycation end-products (AGEs) accumulate in skeletal myofibers of two different animal models of diabesity and whether this accumulation could be associated to myosteatosis. Male C57Bl/6j mice and leptin-deficient ob/ob mice were divided into three groups and underwent 15 weeks of dietary manipulation: standard diet-fed C57 group (C57, n = 10), high-fat high-sugar diet-fed C57 group (HFHS, n = 10), and standard diet-fed ob/ob group (OB/OB, n = 8). HFHS mice and OB/OB mice developed glycometabolic abnormalities in association with decreased mass of the gastrocnemius muscle, fast-to-slow transition of muscle fibers, and lipid accumulation (that occurred preferentially in slow compared to fast fibers). Moreover, we found in muscle fibers of HFHS and OB/OB mice accumulation of AGEs that was preferential for the lipid-accumulating cells, increased expression of the lipogenic pathway SCAP/SREBP, and co-localisation between AGEs and SCAP-(hyper)expressing cells (suggestive for SCAP glycosylation). The increased expression of the SCAP/SREBP lipogenic pathway in muscle fibers is a possible mechanism underlying lipid accumulation and linking myosteatosis to muscle fiber atrophy and fast-to-slow transition that occur in response to diabesity.

Delayed Intervention With Pyridoxamine Improves Metabolic Function and Prevents Adipose Tissue Inflammation and Insulin Resistance in High-Fat Diet–Induced Obese Mice

“…As both SREBP-1C and PPARg expression and the expression of their target genes are decreased, this suggests an inhibitory effect of PM on adipogenesis, possibly via the inhibition of SREBP-1C. In the literature, it has been described that the AGE N(e)-(carboxymethyl) lysine (CML) interferes with the SCAP/SREBP-1C pathway (17,18). In our study, we did not find any effect of PM on mRNA expression levels of SCAP in adipocytes.…”

“…In our study, we did not find any effect of PM on mRNA expression levels of SCAP in adipocytes. However, in different cell types CML has been described to colocalize with SCAP (17)(18)(19), suggesting a considerable glycation of SCAP, and consequently leading to altered function of SCAP. Therefore, the glycation of SCAP, along with the possible direct effects of PM, may be a possible mechanism by which AGEs enhance adipogenesis.…”

The LepRdb/db mice model for studying glycation in the context of diabetes

“…Only a few rodent models have been used to specifically study glycation. Of note are the chemically induced type 1 diabetes (T1D) models, generated by administering streptozotocine (STZ); the genetically induced models of obesity with spontaneous T2D obtained by monogenic mutation, such as the Lep ob/ob mice (deficient in leptin) and the LepR db/db mice (lacking the functional, full‐length Ob‐Rb leptin receptor); and the diet‐induced obesity models (DIO) raised on a high fat (HF) or a high fat‐high sucrose diet (HF‐HS) …”

“…Among the DIO models of T2D, HF and HF‐HS diets have successfully rendered the animals intolerant to glucose but have mixed results with respect to inducing hyperglycaemia. Very few studies have used DIO models to observe the accumulation of AGEs in fluids, tissues, and organs …”

Long-term, but not short-term high-fat diet induces fiber composition changes and impaired contractile force in mouse fast-twitch skeletal muscle

“…Although a recent study showed that 16 weeks on a HFD decreased the number of type IIb fibers and increased the number of type IIa fibers without assessing muscle contraction force (Mastrocola et al. ), the effect of a long‐term HFD on muscle fiber composition and muscle contractile force have not yet been fully elucidated.…”