Abnormal protein turnover and anabolic resistance to exercise in sarcopenic obesity

Nilsson, Mats I.; Dobson, Justin P.; Greene, Nicholas P.; Wiggs, Michael P.; Shimkus, Kevin L.; Wudeck, Elyse V.; Davis, Amanda R.; Laureano, Marissa; Fluckey, James D.

doi:10.1096/fj.12-224006

Cited by 78 publications

(85 citation statements)

References 78 publications

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“…Consistent with the current finding that skeletal muscle from obese, T2D humans exhibit hyperactive mTORC1 signaling, our laboratory (18,19) and others (53,64,72,73) have reported similar findings in skeletal muscle from obese or insulin-resistant mouse models. Similarly, findings have been reported in adipocytes from lean vs. obese individuals (55).…”

Section: R859supporting

confidence: 90%

Aberrant REDD1-mTORC1 responses to insulin in skeletal muscle from Type 2 diabetics

Williamson

Dungan

Mahmoud

et al. 2015

American Journal of Physiology-Regulatory, Integrative and Comp

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-The objective of this study was to establish whether alterations in the REDD1-mTOR axis underlie skeletal muscle insensitivity to insulin in Type 2 diabetic (T2D), obese individuals. Vastus lateralis muscle biopsies were obtained from lean, control and obese, T2D subjects under basal and after a 2-h hyperinsulinemic (40 mU·m Ϫ2 ·min Ϫ1 )-euglycemic (5 mM) clamp. Muscle lysates were examined for total REDD1, and phosphorylated Akt, S6 kinase 1 (S6K1), 4E-BP1, ERK1/2, and MEK1/2 via Western blot analysis. Under basal conditions [(-) insulin], T2D muscle exhibited higher S6K1 and ERK1/2 and lower 4E-BP1 phosphorylation (P Ͻ 0.05), as well as elevations in blood cortisol, glucose, insulin, glycosylated hemoglobin (P Ͻ 0.05) vs. lean controls. Following insulin infusion, whole body glucose disposal rates (GDR; mg/kg/ min) were lower (P Ͻ 0.05) in the T2D vs. the control group. The basal-to-insulin percent change in REDD1 expression was higher (P Ͻ 0.05) in muscle from the T2D vs. the control group. Whereas, the basal-to-insulin percent change in muscle Akt, S6K1, ERK1/2, and MEK1/2 phosphorylation was significantly lower (P Ͻ 0.05) in the T2D vs. the control group. Findings from this study propose a REDD1-regulated mechanism in T2D skeletal muscle that may contribute to whole body insulin resistance and may be a target to improve insulin action in insulin-resistant individuals.glucocorticoid; insulin resistance; mTOR; signaling TWO-THIRDS OF THE UNITED STATES has a 25% or greater prevalence of obesity (54), which places increased demand and cost on the health care system. Of the numerous comorbidities associated with obesity, the development of insulin resistance and Type 2 diabetes (T2D) are major concern for obese individuals, leading to overall reductions in metabolic flexibility (50). This becomes more of a concern, since the population of obese individuals is expanding in all age groups. Findings from the National Health and Nutrition Examination Survey data (68,69) show that skeletal muscle mass is fundamental for insulin sensitivity. Skeletal muscle mass is lower in the obese when expressed relative to total body mass vs. a lean individual and has a high pervasiveness of ectopic lipid within skeletal muscle that contributes to reduced insulin action (27,50). Among other factors, elevated endogenous glucocorticoid concentrations contribute to insulin resistance in the obese and T2D (58, 74).Insulin activation of the insulin receptor substrate 1 (IRS-1), phosphatidyl-inositol-3 kinase (PI3K), Ak strain transforming (Akt), and the ERK 1/2 pathways are essential for the regulation of cellular glucose uptake, proliferation, and growth. Akt and ERK1/2 activation increases GTPase function of the Ras homolog enriched in brain (Rheb) protein toward the mechanistic target of rapamycin (mTOR; also known as mammalian target of rapamycin) by inactivating the repressive effects of the tuberous sclerosis complex (TSC). The TSC complex remains central to the integration of signaling inputs from Akt, ERK1/2, and AMPK (32, 44,...

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Section: R859supporting

confidence: 90%

Aberrant REDD1-mTORC1 responses to insulin in skeletal muscle from Type 2 diabetics

Williamson

Dungan

Mahmoud

et al. 2015

American Journal of Physiology-Regulatory, Integrative and Comp

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“…However, in the absence of biopsies taken prior to initiation of the exercise training in the Labrador Retrievers, it is hard to make this determination. Although there is evidence from rodents that weight gain does not selectively change the synthesis rates of protein fractions (16), it is unknown whether this is true in dogs.…”

Section: Discussionmentioning

confidence: 99%

“…Longer periods of assessment are limited by the need to maintain a constant infusion of isotopes, thus restricting freeliving conditions. To address these limitations, we (4,5,13,14,19,22) and others (2,6,16,26) have employed stable isotope techniques that use deuterium oxide ( 2 H 2 O). By providing 2 H 2 O in the drinking water of humans (19,22) or rodents (4,5,13,14), we have assessed cumulative protein synthesis over the period of weeks, rather than hours.…”

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confidence: 99%

Assessment of protein synthesis in highly aerobic canine species at the onset and during exercise training

Miller

Ehrlicher

Drake

et al. 2015

Journal of Applied Physiology

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Miller BF, Ehrlicher SE, Drake JC, Peelor FF 3rd, Biela LM, Pratt-Phillips S, Davis M, Hamilton KL. Assessment of protein synthesis in highly aerobic canine species at the onset and during exercise training. J Appl Physiol 118: 811-817, 2015. First published January 22, 2015 doi:10.1152/japplphysiol.00982.2014.-Canis lupus familiaris, the domesticated dog, is capable of extreme endurance performance. The ability to perform sustained aerobic exercise is dependent on a well-developed mitochondrial reticulum. In this study we examined the cumulative muscle protein and DNA synthesis in groups of athletic dogs at the onset of an exercise training program and following a strenuous exercise training program. We hypothesized that both at the onset and during an exercise training program there would be greater mitochondrial protein synthesis rates compared with sedentary control with no difference in mixed or cytoplasmic protein synthesis rates. Protein synthetic rates of three protein fractions and DNA synthesis were determined over 1 wk using 2 H2O in competitive Alaskan Huskies and Labrador Retrievers trained for explosive device detection. Both groups of dogs had very high rates of skeletal muscle protein synthesis in the sedentary state [Alaskan Huskies: Mixed ϭ 2.28 Ϯ 0.12, cytoplasmic (Cyto) ϭ 2.91 Ϯ 0.10, and mitochondrial (Mito) ϭ 2.62 Ϯ 0.07; Labrador Retrievers: Mixed ϭ 3.88 Ϯ 0.37, Cyto ϭ 3.85 Ϯ 0.06, and Mito ϭ 2.92 Ϯ 0.20%/day]. Mitochondrial (Mito) protein synthesis rates did not increase at the onset of an exercise training program. Exercise-trained dogs maintained Mito protein synthesis during exercise training when mixed (Mixed) and cytosolic (Cyto) fractions decreased, and this coincided with a decrease in p-RpS6 but also a decrease in p-ACC signaling. Contrary to our hypothesis, canines did not have large increases in mitochondrial protein synthesis at the onset or during an exercise training program. However, dogs have a high rate of protein synthesis compared with humans that perhaps does not necessitate an extra increase in protein synthesis at the onset of aerobic exercise training.comparative; deuterium oxide; dogs; exercise; stable isotope CANIS LUPUS FAMILIARIS, the domesticated dog, is capable of extreme endurance exercise performance. At the annual Iditarod Race, winning sled dog teams can cover 1,600 km in less than 9 days. When the energetic demands of this extreme activity are combined with environmental stress, total energy expenditure approximates 50,000 kJ/d (7), which far exceeds, on a relative and absolute basis, the highest values recorded in humans [Tour de France cyclists (25)]. Although the ability to sustain these high energy expenditures may be unique to Alaskan Huskies, other canine breeds also have a large aerobic capacity as is evident by a maximal oxygen consumption (V O 2max ) of 145.8 ml·kg Ϫ1 ·min Ϫ1 recorded in Labrador Retrievers (18) and 240 ml·kg Ϫ1

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“…[22] In addition, insulin resistance may contribute to the muscle loss in diabetes, by inactivating the mammalian target of rapamycin (mTOR) pathway and stimulating autophagy. [23,24] A recent experimental study by Nilsson et al [25] showed that level of the domain-containing mTOR-interacting protein (DEPTOR), an endogenous mTOR inhibitor, was critical in the regulation of protein turnover in sarcopenic obese rats. Not only skeletal muscle size and mass reduced, bioenergy systems of the body including mitochondrial function may be also altered in these patients.…”

Section: Discussionmentioning

confidence: 99%

The effect of blood glucose regulation on sarcopenia parameters in obese and diabetic patients

Öztürk

Türkbeyler

Demir

et al. 2017

Turk J Phys Med Rehab

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The effect of blood glucose regulation on sarcopenia parameters in obese and diabetic patients. Turk J Phys Med Rehab 2018;64(1):72-79. ABSTRACTObjectives: This study aims to evaluate the effect of blood glucose regulation on sarcopenia parameters in sarcopenic, obese, and poorlyregulated diabetic patients. Patients and methods:Between June 2013 and December 2013, a total of 147 patients (64 males, 83 females; mean age 70.3±6.3 years; range, 60 to 90 years) who were diagnosed with sarcopenia according to the European Working Group on Sarcopenia in Older People (EWGSOP) criteria were included in the study. All patients were obese with a body mass index (BMI) of >30 kg/m 2 and their glycated hemoglobin (HbA1c) levels were above 8%. Sarcopenia parameters including the gait speed, muscle strength, muscle mass, and handgrip strength were assessed. After a six-month treatment period, the patients were divided into two groups according to their HbA1c levels as having <8% or >8%. Sarcopenia parameters were evaluated before and after receiving treatment. Results:The mean disease duration was 16±6.2 years. Sixty patients were found to have a HbA1c level of <8% and 45 patients with a HbA1c level of ≥8% at sixth months of follow-up. In better regulated group, sarcopenia parameters such as gait speed, muscle mass, and handgrip strength improved; however, only the change in the muscle mass was found to be statistically significant (p=0.041). There was no significant change in the parameters of sarcopenia in the patient group with a HbA1c level ≥8%. A negative correlation was found between the muscle mass and HbA1c levels in good-and poorly-regulated groups (p=0.039 r:-0.327 and p=0.044 r:-0.183, respectively). Conclusion:Our study demonstrates that lowering HbA1c levels may have positive effects on the muscle mass even in diabetic and sarcopenic obese elderly individuals.

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Abnormal protein turnover and anabolic resistance to exercise in sarcopenic obesity

Cited by 78 publications

References 78 publications

Aberrant REDD1-mTORC1 responses to insulin in skeletal muscle from Type 2 diabetics

Aberrant REDD1-mTORC1 responses to insulin in skeletal muscle from Type 2 diabetics

Assessment of protein synthesis in highly aerobic canine species at the onset and during exercise training

The effect of blood glucose regulation on sarcopenia parameters in obese and diabetic patients

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