scholarly journals Is There a Metabolic Program in the Skeletal Muscle of Obese Individuals?

2011 ◽  
Vol 2011 ◽  
pp. 1-11 ◽  
Author(s):  
Joseph A. Houmard ◽  
Walter J. Pories ◽  
G. Lynis Dohm
Keyword(s):  
Skeletal Muscle ◽  
Insulin Action ◽  
Human Skeletal Muscle ◽  
Bypass Surgery ◽  
Severe Obesity ◽  
Gastric Bypass Surgery ◽  
Acid Oxidation ◽  
Genetic Origin ◽  
Human Skeletal Muscle Cells ◽  
Severely Obese

Severe obesity (BMI ≥ 40 kg/m2) is associated with multiple defects in skeletal muscle which contribute to insulin resistance and a reduction in fatty acid oxidation (FAO) in this tissue. These metabolic derangements are retained in human skeletal muscle cells raised in culture. Together, these findings are indicative of a dysfunctional global metabolic program with severe obesity which is of an epigenetic or genetic origin. Weight loss via gastric bypass surgery can “turn off” and/or correct components of this metabolic program as insulin sensitivity is restored; however, the impairment in FAO in skeletal muscle remains evident. Physical activity can improve FAO and insulin action, indicating that this patient population is not exercise resistant and that exercise offers a pathway to circumvent the abnormal program. Findings presented in this review will hopefully increase the understanding of and aid in preventing and/or treating the severely obese condition.

Does impaired mitochondrial function affect insulin signaling and action in cultured human skeletal muscle cells?

2008 ◽  
Vol 294 (1) ◽  
pp. E97-E102 ◽  
Author(s):  
Audrey E. Brown ◽  
Matthias Elstner ◽  
Stephen J. Yeaman ◽  
Douglass M. Turnbull ◽  
Mark Walker
Keyword(s):  
Skeletal Muscle ◽  
Glucose Uptake ◽  
Insulin Signaling ◽  
Mitochondrial Respiration ◽  
Respiratory Function ◽  
Insulin Action ◽  
Human Skeletal Muscle ◽  
Human Skeletal Muscle Cells ◽  
Basal Glucose Uptake

Insulin-resistant type 2 diabetic patients have been reported to have impaired skeletal muscle mitochondrial respiratory function. A key question is whether decreased mitochondrial respiration contributes directly to the decreased insulin action. To address this, a model of impaired cellular respiratory function was established by incubating human skeletal muscle cell cultures with the mitochondrial inhibitor sodium azide and examining the effects on insulin action. Incubation of human skeletal muscle cells with 50 and 75 μM azide resulted in 48 ± 3% and 56 ± 1% decreases, respectively, in respiration compared with untreated cells mimicking the level of impairment seen in type 2 diabetes. Under conditions of decreased respiratory chain function, insulin-independent (basal) glucose uptake was significantly increased. Basal glucose uptake was 325 ± 39 pmol/min/mg (mean ± SE) in untreated cells. This increased to 669 ± 69 and 823 ± 83 pmol/min/mg in cells treated with 50 and 75 μM azide, respectively (vs. untreated, both P < 0.0001). Azide treatment was also accompanied by an increase in basal glycogen synthesis and phosphorylation of AMP-activated protein kinase. However, there was no decrease in glucose uptake following insulin exposure, and insulin-stimulated phosphorylation of Akt was normal under these conditions. GLUT1 mRNA expression remained unchanged, whereas GLUT4 mRNA expression increased following azide treatment. In conclusion, under conditions of impaired mitochondrial respiration there was no evidence of impaired insulin signaling or glucose uptake following insulin exposure in this model system.

scholarly journals Overexpression of Long-Chain Acyl-CoA Synthetase 5 Increases Fatty Acid Oxidation and Free Radical Formation While Attenuating Insulin Signaling in Primary Human Skeletal Myotubes

2019 ◽  
Vol 16 (7) ◽  
pp. 1157 ◽  
Author(s):  
Hyo-Bum Kwak ◽  
Tracey Woodlief ◽  
Thomas Green ◽  
Julie Cox ◽  
Robert Hickner ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Fatty Acid ◽  
Free Radical ◽  
Fatty Acid Oxidation ◽  
Insulin Signaling ◽  
Human Skeletal Muscle ◽  
Acid Oxidation ◽  
Protein Levels ◽  
Human Skeletal Muscle Cells ◽  
Mitochondrial Fatty Acid

In rodent skeletal muscle, acyl-coenzyme A (CoA) synthetase 5 (ACSL-5) is suggested to localize to the mitochondria but its precise function in human skeletal muscle is unknown. The purpose of these studies was to define the role of ACSL-5 in mitochondrial fatty acid metabolism and the potential effects on insulin action in human skeletal muscle cells (HSKMC). Primary myoblasts isolated from vastus lateralis (obese women (body mass index (BMI) = 34.7 ± 3.1 kg/m2)) were transfected with ACSL-5 plasmid DNA or green fluorescent protein (GFP) vector (control), differentiated into myotubes, and harvested (7 days). HSKMC were assayed for complete and incomplete fatty acid oxidation ([1-14C] palmitate) or permeabilized to determine mitochondrial respiratory capacity (basal (non-ADP stimulated state 4), maximal uncoupled (carbonyl cyanide-4-(trifluoromethoxy)phenylhydrazone (FCCP)-linked) respiration, and free radical (superoxide) emitting potential). Protein levels of ACSL-5 were 2-fold higher in ACSL-5 overexpressed HSKMC. Both complete and incomplete fatty acid oxidation increased by 2-fold (p < 0.05). In permeabilized HSKMC, ACSL-5 overexpression significantly increased basal and maximal uncoupled respiration (p < 0.05). Unexpectedly, however, elevated ACSL-5 expression increased mitochondrial superoxide production (+30%), which was associated with a significant reduction (p < 0.05) in insulin-stimulated p-Akt and p-AS160 protein levels. We concluded that ACSL-5 in human skeletal muscle functions to increase mitochondrial fatty acid oxidation, but contrary to conventional wisdom, is associated with increased free radical production and reduced insulin signaling.

scholarly journals Alterations of sorbin and SH3 domain containing 3 (SORBS3) in human skeletal muscle following Roux-en-Y gastric bypass surgery

2017 ◽  
Vol 9 (1) ◽  
Author(s):  
Samantha E. Day ◽  
Luis A. Garcia ◽  
Richard L. Coletta ◽  
Latoya E. Campbell ◽  
Tonya R. Benjamin ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Gastric Bypass ◽  
Human Skeletal Muscle ◽  
Bypass Surgery ◽  
Gastric Bypass Surgery ◽  
Sh3 Domain

Knockdown of PRAS40 inhibits insulin action via proteasome-mediated degradation of IRS1 in primary human skeletal muscle cells

Diabetologia ◽  
2013 ◽  
Vol 56 (5) ◽  
pp. 1118-1128 ◽  
Author(s):  
C. Wiza ◽  
D. Herzfeld de Wiza ◽  
E. B. M. Nascimento ◽  
S. Lehr ◽  
H. Al-Hasani ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Insulin Action ◽  
Human Skeletal Muscle ◽  
Muscle Cells ◽  
Skeletal Muscle Cells ◽  
Human Skeletal Muscle Cells

scholarly journals Roux-en-Y gastric bypass surgery enhances contraction-mediated glucose metabolism in primary human myotubes

2017 ◽  
Vol 313 (2) ◽  
pp. E195-E202 ◽  
Author(s):  
J. Matthew Hinkley ◽  
Kai Zou ◽  
Sanghee Park ◽  
Kristen Turner ◽  
Donghai Zheng ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Gastric Bypass ◽  
Body Mass ◽  
Insulin Action ◽  
Glucose Oxidation ◽  
Contractile Activity ◽  
Gastric Bypass Surgery ◽  
Glycogen Synthesis ◽  
Human Myotubes ◽  
Severely Obese

Contractile activity (e.g., exercise) evokes numerous metabolic adaptations in human skeletal muscle, including enhanced insulin action and substrate oxidation. However, there is intersubject variation in the physiological responses to exercise, which may be linked with factors such as the degree of obesity. Roux-en-Y gastric bypass (RYGB) surgery reduces body mass in severely obese (body mass index ≥ 40 kg/m2) individuals; however, it is uncertain whether RYGB can potentiate responses to contractile activity in this potentially exercise-resistant population. To examine possible interactions between RYGB and contractile activity, muscle biopsies were obtained from severely obese patients before and after RYGB, differentiated into myotubes, and electrically stimulated, after which changes in insulin action and glucose oxidation were determined. Before RYGB, myotubes were unresponsive to electrical stimulation, as indicated by no changes in insulin-stimulated glycogen synthesis and basal glucose oxidation. However, myotubes from the same patients at 1 mo after RYGB increased insulin-stimulated glycogen synthesis and basal glucose oxidation when subjected to contraction. While unresponsive before surgery, contraction improved insulin-stimulated phosphorylation of AS160 (Thr642, Ser704) after RYGB. These data suggest that RYGB surgery may enhance the ability of skeletal muscle from severely obese individuals to respond to contractile activity.

GRB14, GPD1, and GDF8 as potential network collaborators in weight loss-induced improvements in insulin action in human skeletal muscle

2006 ◽  
Vol 27 (2) ◽  
pp. 114-121 ◽  
Author(s):  
Jung-Jun Park ◽  
Jason R. Berggren ◽  
Matthew W. Hulver ◽  
Joseph A Houmard ◽  
Eric P. Hoffman
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Weight Loss ◽  
Gastric Bypass ◽  
Insulin Action ◽  
Bypass Surgery ◽  
Gastric Bypass Surgery ◽  
Morbidly Obese ◽  
Obese Women ◽  
Cross Sectional

Obesity is associated with insulin resistance in skeletal muscle; accordingly, weight loss dramatically improves insulin action. We sought to identify molecular remodeling of muscle commensurate with weight loss that could explain improvements in insulin action. Muscle from morbidly obese women was studied before and after gastric bypass surgery. Gastric bypass surgery significantly reduced body mass by ∼45% and improved insulin action. We then assessed mRNA profiles using a stringent statistical analysis (statistical concordance with three probe set algorithms), with validation in a cross-sectional study of lean ( n = 8) vs. morbidly obese ( n = 8) muscle. Growth factor receptor-bound protein 14 (GRB14), glycerol-3-phosphate dehydrogenase 1 (GPD1), and growth differentiation factor 8 (GDF8; myostatin) significantly decreased ∼2.4-, 2.2-, and 2.4-fold, respectively, after weight loss (gastric bypass). Increased expression of these transcripts was associated with increased obesity in the cross-sectional group (lean vs. morbidly obese muscle). Each transcript was validated by real-time quantitative RT-PCR assays in both study groups. Using Ingenuity Pathway Analysis, we show that all three transcripts are involved in the same regulatory network including AKT1, IGF1, TNF, PPARG, and INS. These results suggest that GRB14, GPD1, and GDF8 are weight loss-responsive genes in skeletal muscle and that the observed transcriptional modulation of these would be expected to improve insulin signaling, decrease triglyceride synthesis, and increase muscle mass, respectively, with weight loss. Thus our data provide a possible regulatory pathway involved in the development of insulin resistance in the morbidly obese state, and improvement of insulin resistance with weight loss.

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