Single‐leg exercise training augments in vivo skeletal muscle oxidative flux and vascular content and function in adults with type 2 diabetes

Skeletal muscle microvascular dysfunction and mitochondrial rarefaction feature in type-2 diabetes mellitus (T2DM) linked to low tissue glucose disposal rate (GDR). Exercise training and milk protein supplementation independently promote microvascular and metabolic plasticity in muscle associated with improved nutrient delivery, but combined effects are unknown. In a randomised-controlled trial, 24 men (55.6 y, SD5.7) with T2DM ingested whey protein drinks (protein/carbohydrate/fat: 20/10/3 g; WHEY) or placebo (carbohydrate/fat: 30/3 g; CON) before/after 45 mixed-mode intense exercise sessions over 10 weeks, to study effects on insulin-stimulated (hyperinsulinemic clamp) skeletal-muscle microvascular blood flow (mBF) and perfusion (near-infrared spectroscopy), and histological, genetic, and biochemical markers (biopsy) of microvascular and mitochondrial plasticity. WHEY enhanced insulin-stimulated perfusion (WHEY-CON 5.6%; 90%CI -0.1, 11.3), while mBF was not altered (3.5%; -17.5, 24.5); perfusion, but not mBF, associated (regression) with increased GDR. Exercise training increased mitochondrial (range of means: 40-90%) and lipid density (20-30%), enzyme activity (20-70%), capillary:fiber ratio (~25%), and lowered systolic (~4%) and diastolic (4-5%) blood pressure, but without WHEY effects. WHEY dampened PGC1α -2.9% (90%CI -5.7, -0.2) and NOS3 -6.4% (-1.4, -0.2) expression, but other mRNA were unclear. Skeletal muscle microvascular and mitochondrial exercise adaptations were not accentuated by whey protein ingestion in men with T2DM. Clinical Trial Registration Number: ACTRN12614001197628 Novelty Bullets: • Chronic whey ingestion in T2DM with exercise altered expression of several mitochondrial and angiogenic mRNA. • Whey added no additional benefit to muscle microvascular or mitochondrial adaptations to exercise. • Insulin-stimulated perfusion increased with whey but was without impact on glucose disposal.

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Dysfunction of muscle contraction with impaired intracellular Ca2+ handling in skeletal muscle and the effect of exercise training in male db/db mice

Journal of Applied Physiology ◽

10.1152/japplphysiol.00048.2018 ◽

2019 ◽

Vol 126 (1) ◽

pp. 170-182 ◽

Cited By ~ 6

Author(s):

Hiroaki Eshima ◽

Yoshifumi Tamura ◽

Saori Kakehi ◽

Kyoko Nakamura ◽

Nagomi Kurebayashi ◽

...

Keyword(s):

Type 2 Diabetes ◽

Skeletal Muscle ◽

Exercise Training ◽

Muscle Contraction ◽

Contractile Function ◽

Contractile Force ◽

Contractile Dysfunction ◽

Muscle Contractile ◽

Type 2 Diabetic

Type 2 diabetes is characterized by reduced contractile force production and increased fatigability of skeletal muscle. While the maintenance of Ca2+ homeostasis during muscle contraction is a requisite for optimal contractile function, the mechanisms underlying muscle contractile dysfunction in type 2 diabetes are unclear. Here, we investigated skeletal muscle contractile force and Ca2+ flux during contraction and pharmacological stimulation in type 2 diabetic model mice ( db/db mice). Furthermore, we investigated the effect of treadmill exercise training on muscle contractile function. In male db/db mice, muscle contractile force and peak Ca2+ levels were both lower during tetanic stimulation of the fast-twitch muscles, while Ca2+ accumulation was higher after stimulation compared with control mice. While 6 wk of exercise training did not improve glucose tolerance, exercise did improve muscle contractile dysfunction, peak Ca2+ levels, and Ca2+ accumulation following stimulation in male db/db mice. These data suggest that dysfunctional Ca2+ flux may contribute to skeletal muscle contractile dysfunction in type 2 diabetes and that exercise training may be a promising therapeutic approach for dysfunctional skeletal muscle contraction. NEW & NOTEWORTHY The purpose of this study was to examine muscle contractile function and Ca2+ regulation as well as the effect of exercise training in skeletal muscle in obese diabetic mice ( db/db). We observed impairment of muscle contractile force and Ca2+ regulation in a male type 2 diabetic animal model. These dysfunctions in muscle were improved by 6 wk of exercise training.

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Reduced Skeletal Muscle Inhibitor of B Content Is Associated With Insulin Resistance in Subjects With Type 2 Diabetes: Reversal by Exercise Training

Diabetes ◽

10.2337/diabetes.55.03.06.db05-0677 ◽

2006 ◽

Vol 55 (3) ◽

pp. 760-767 ◽

Cited By ~ 87

Author(s):

A. Sriwijitkamol ◽

C. Christ-Roberts ◽

R. Berria ◽

P. Eagan ◽

T. Pratipanawatr ◽

...

Keyword(s):

Insulin Resistance ◽

Type 2 Diabetes ◽

Skeletal Muscle ◽

Exercise Training

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226-OR: ADA Presidents’ Select Abstract: Exercise Training Promotes Mitochondrial Remodeling in Skeletal Muscle of Type 2 Diabetes Humans

Diabetes ◽

10.2337/db21-226-or ◽

2021 ◽

Vol 70 (Supplement 1) ◽

pp. 226-OR

Author(s):

LUCIA MASTROTOTARO ◽

MARIA APOSTOLOPOULOU ◽

DOMINIK PESTA ◽

KLAUS STRASSBURGER ◽

YANISLAVA KARUSHEVA ◽

...

Keyword(s):

Type 2 Diabetes ◽

Skeletal Muscle ◽

Exercise Training ◽

Select Abstract ◽

Mitochondrial Remodeling

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Mitochondrial dysfunction and insulin resistance from the outside in: extracellular matrix, the cytoskeleton, and mitochondria

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00363.2011 ◽

2011 ◽

Vol 301 (5) ◽

pp. E749-E755 ◽

Cited By ~ 55

Author(s):

Dawn K. Coletta ◽

Lawrence J. Mandarino

Keyword(s):

Insulin Resistance ◽

Type 2 Diabetes ◽

Skeletal Muscle ◽

Extracellular Matrix ◽

Contractile Activity ◽

Cytoskeletal Proteins ◽

Altered Expression ◽

Insulin Resistant ◽

And Function

Insulin resistance in skeletal muscle is a prominent feature of obesity and type 2 diabetes. The association between mitochondrial changes and insulin resistance is well known. More recently, there is growing evidence of a relationship between inflammation, extracellular remodeling, and insulin resistance. The intent of this review is to propose a potentially novel mechanism for the development of insulin resistance, focusing on the underappreciated connections among inflammation, extracellular remodeling, cytoskeletal interactions, mitochondrial function, and insulin resistance in human skeletal muscle. Several sources of inflammation, including expansion of adipose tissue resulting in increased lipolysis and alterations in pro- and anti-inflammatory cytokines, contribute to the insulin resistance observed in obesity and type 2 diabetes. In the experimental model of lipid oversupply, an inflammatory response in skeletal muscle leads to altered expression extracellular matrix-related genes as well as nuclear encoded mitochondrial genes. A similar pattern also is observed in “naturally” occurring insulin resistance in muscle of obese nondiabetic individuals and patients with type 2 diabetes mellitus. More recently, alterations in proteins (including α-actinin-2, desmin, proteasomes, and chaperones) involved in muscle structure and function have been observed in insulin-resistant muscle. Some of these cytoskeletal proteins are mechanosignal transducers that allow muscle fibers to sense contractile activity and respond appropriately. The ensuing alterations in expression of genes coding for mitochondrial proteins and cytoskeletal proteins may contribute to the mitochondrial changes observed in insulin-resistant muscle. These changes in turn may lead to a reduction in fat oxidation and an increase in intramyocellular lipid, which contributes to the defects in insulin signaling in insulin resistance.

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Leptin Enhances Insulin Sensitivity by Direct and Sympathetic Nervous System Regulation of Muscle IGFBP-2 Expression: Evidence From Nonrodent Models

Endocrinology ◽

10.1210/en.2013-2099 ◽

2014 ◽

Vol 155 (6) ◽

pp. 2133-2143 ◽

Cited By ~ 31

Author(s):

Steven W. Yau ◽

Belinda A. Henry ◽

Vincenzo C. Russo ◽

Glenn K. McConell ◽

Iain J. Clarke ◽

...

Keyword(s):

Type 2 Diabetes ◽

Skeletal Muscle ◽

Nervous System ◽

Insulin Sensitivity ◽

Sympathetic Nervous System ◽

Insulin Signaling ◽

In Vivo Experiments ◽

Sympathetic Nervous

Leptin is produced from white adipose tissue and acts primarily to regulate energy balance. Obesity is associated with leptin resistance and increased circulating levels of leptin. Leptin has recently been shown to influence levels of IGF binding protein-2 (IGFBP-2), a protein that is reduced in obesity and type 2 diabetes. Overexpression of IGFBP-2 protects against obesity and type 2 diabetes. As such, IGFBP-2 signaling may represent a novel pathway by which leptin regulates insulin sensitivity. We sought to investigate how leptin regulates skeletal muscle IGFBP-2 levels and to assess the impact of this on insulin signaling and glucose uptake. In vitro experiments were undertaken in cultured human skeletal myotubes, whereas in vivo experiments assessed the effect of intracerebroventricular leptin on peripheral skeletal muscle IGFBP-2 expression and insulin sensitivity in sheep. Leptin directly increased IGFBP-2 mRNA and protein in human skeletal muscle through both signal transducer and activator of transcription-3 and phosphatidylinositol 3-kinase signaling, in parallel with enhanced insulin signaling. Silencing IGFBP-2 lowered leptin- and insulin-stimulated protein kinase B phosphorylation and glucose uptake. In in vivo experiments, intracerebroventricular leptin significantly increased hind-limb skeletal muscle IGFBP-2, an effect completely blocked by concurrent peripheral infusion of a β-adrenergic blocking agent. Sheep receiving central leptin showed improvements in glucose tolerance and circulating insulin levels after an iv glucose load. In summary, leptin regulates skeletal muscle IGFBP-2 by both direct peripheral and central (via the sympathetic nervous system) mechanisms, and these likely impact on peripheral insulin sensitivity and glucose metabolism.

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