Skeletal muscle mitochondrial dysfunction is secondary to type 2 diabetes and can be improved by prolonged exercise training

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.

Download Full-text

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.

Download Full-text

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

Download Full-text

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

Download Full-text

Mitochondrial Function in Skeletal Muscle Is Normal and Unrelated to Insulin Action in Young Men Born with Low Birth Weight

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2008-0630 ◽

2008 ◽

Vol 93 (10) ◽

pp. 3885-3892 ◽

Cited By ~ 57

Author(s):

Charlotte Brøns ◽

Christine B. Jensen ◽

Heidi Storgaard ◽

Amra Alibegovic ◽

Stine Jacobsen ◽

...

Keyword(s):

Insulin Resistance ◽

Type 2 Diabetes ◽

Skeletal Muscle ◽

Birth Weight ◽

Low Birth Weight ◽

Mitochondrial Dysfunction ◽

Mitochondrial Function ◽

Young Men ◽

Hepatic Insulin Resistance

Objective: Low birth weight (LBW) is an independent risk factor of insulin resistance and type 2 diabetes. Recent studies suggest that mitochondrial dysfunction and impaired expression of genes involved in oxidative phosphorylation (OXPHOS) may play a key role in the pathogenesis of insulin resistance in aging and type 2 diabetes. The aim of this study was to determine whether LBW in humans is associated with mitochondrial dysfunction in skeletal muscle. Methods: Mitochondrial capacity for ATP synthesis was assessed by 31phosphorus magnetic resonance spectroscopy in forearm and leg muscles in 20 young, lean men with LBW and 26 matched controls. On a separate day, a hyperinsulinemic euglycemic clamp with excision of muscle biopsies and dual-energy x-ray absorptiometry scanning was performed. Muscle gene expression of selected OXPHOS genes was determined by quantitative real-time PCR. Results: The LBW subjects displayed a variety of metabolic and prediabetic abnormalities, including elevated fasting blood glucose and plasma insulin levels, reduced insulin-stimulated glycolytic flux, and hepatic insulin resistance. Nevertheless, in vivo mitochondrial function was normal in LBW subjects, as was the expression of OXPHOS genes. Conclusions: These data support and expand previous findings of abnormal glucose metabolism in young men with LBW. In addition, we found that the young, healthy men with LBW exhibited hepatic insulin resistance. However, the study does not support the hypothesis that muscle mitochondrial dysfunction per se is the underlying key metabolic defect that explains or precedes whole body insulin resistance in LBW subjects at risk for developing type 2 diabetes.

Download Full-text