scholarly journals In a Mouse Model of Type 2 Diabetes and Peripheral Artery Disease, Modulation of MirR29a and ADAM12 Reduced Post -Ischemic Skeletal Muscle Injury, Improved Perfusion Recovery and Skeletal Muscle Function

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. A289-A290
Author(s):  
Victor Lamin ◽  
Thomas Wong ◽  
Aya Babikir ◽  
Joseph Verry ◽  
Isaac Eigner-Bybee ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Skeletal Muscle ◽  
Muscle Function ◽  
Muscle Injury ◽  
Hind Limb ◽  
Diabetic Mice ◽  
Skeletal Muscle Function ◽  
Skeletal Muscle Injury ◽  
Hind Limbs

Abstract Diabetes Mellitus (DM) is a major risk factor for developing peripheral arterial disease (PAD) and individuals with DM have worse PAD outcomes but the molecular mechanisms involved are poorly understood. Previously, in a hind limb ischemia (HLI) model of PAD, we identified a disintegrin and metalloproteinase gene 12 (ADAM12) as a key genetic modifier of post-ischemic perfusion recovery. Moreover, we showed that expression of ADAM12 in mouse and human tissue is regulated by miR29a. In non-diabetic mice, miR29a expression is downregulated after HLI that allows increased expression of ADAM12. However, upon HLI in high fat diet feed (HFD) mice, a model of type 2 diabetes, miR29a expression remains elevated that prevents ADAM12 increase and results in poor reperfusion recovery, increased skeletal muscle injury and decreased muscle function. Hence, we hypothesized that inhibition of miR29a or augmenting ADAM12 would improve these functional outcomes. Mice (male, 26–28 weeks old) were randomized into 3 treatment groups and their hind limbs were treated with saline (grp1), ADAM12 cDNA (grp 2) or mir29a-inhibitor (grp3), through targeted micro-bubble delivery. Mice were treated at -3 days and -1 pre-surgery, followed by post-surgery weekly boosting. HLI was achieved by unilateral ligation and excision of the femoral artery of the left hind limb. The right hind limb served as non-ischemic control. Gene expression analysis in the hind limbs 3 days post HLI showed decreased miR29a expression in normal chow fed B6, but elevated miR29a expression in HFD (B6 vs HFD; 0.5730±0.01 vs.1.02 ± 0.06, n=3–4, p= 0.001). Treatment with miR29a inhibitor decreased miR29a expression in HFD and increased ADAM12 expression compared to control untreated HFD mice (miR29a INH vs Control HFD: 0.70±0.06 vs 1.02±0.06, n= 4–5, p= 0.004) ADAM12 expression (miR29A INH vs Control: HFD 208.62±24.52 vs 11.75±4.94, n= 3–4 P<0.01). Although ADAM12 cDNA improved ADAM12 expression, miR29a inhibition increased ADAM12 expression to a greater extent (HFD vs ADAM12 vs miR29aINH; 11.75±4.94 vs 20.71±2.98 vs 208.62±24.52, n3-4, p=< 0.001). Accordingly, miR29a inhibition and ADAM12 augmentation decreased skeletal muscle injury assessed by the number of centralized nuclei/muscle fibre (Control vs ADAM12 vs miR29aINH: 0.252±0.043, vs 0.139±0.041 vs 0.040±0.012 n=4, p= 0.05), and improved skeletal muscle function assessed as maximum muscle contraction (Control vs ADAM12 vs miR29aINH: 0.17±0.06 vs 0.26±0.06, vs 0.54±0.08, n=6–7, p<0.01). It also improved perfusion recovery, (% ischemic to non-ischemic limb, control vs ADAM12 vs miR29aINH: 42.52±5.35, vs 58.45±4.87, vs 97.59±6.14, n= 5–10, p<0.01). Thus, our results show augmentation of ADAM12 and Inhibition of MiR29a improves outcomes in experimental PAD in diabetic mice but inhibiting miR29a is a more effective strategy. 2414 characters now2500 characters allowed

scholarly journals Modulation of miR-29a and ADAM12 Reduces Post-Ischemic Skeletal Muscle Injury and Improves Perfusion Recovery and Skeletal Muscle Function in a Mouse Model of Type 2 Diabetes and Peripheral Artery Disease

2021 ◽  
Vol 23 (1) ◽  
pp. 429
Author(s):  
Victor Lamin ◽  
Joseph Verry ◽  
Isaac Eigner-Bybee ◽  
Jordan D. Fuqua ◽  
Thomas Wong ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Type 2 Diabetes ◽  
Skeletal Muscle ◽  
Muscle Function ◽  
Muscle Injury ◽  
Genetic Modifier ◽  
Limb Amputation ◽  
Skeletal Muscle Injury ◽  
Increased Risk

Both Type 1 diabetes mellitus (DM1) and type 2 diabetes mellitus (DM2) are associated with an increased risk of limb amputation in peripheral arterial disease (PAD). How diabetes contributes to poor PAD outcomes is poorly understood but may occur through different mechanisms in DM1 and DM2. Previously, we identified a disintegrin and metalloproteinase gene 12 (ADAM12) as a key genetic modifier of post-ischemic perfusion recovery. In an experimental PAD, we showed that ADAM12 is regulated by miR-29a and this regulation is impaired in ischemic endothelial cells in DM1, contributing to poor perfusion recovery. Here we investigated whether miR-29a regulation of ADAM12 is altered in experimental PAD in the setting of DM2. We also explored whether modulation of miR-29a and ADAM12 expression can improve perfusion recovery and limb function in mice with DM2. Our result showed that in the ischemic limb of mice with DM2, miR-29a expression is poorly downregulated and ADAM12 upregulation is impaired. Inhibition of miR-29a and overexpression of ADAM12 improved perfusion recovery, reduced skeletal muscle injury, improved muscle function, and increased cleaved Tie 2 and AKT phosphorylation. Thus, inhibition of miR-29a and or augmentation of ADAM12 improves experimental PAD outcomes in DM2 likely through modulation of Tie 2 and AKT signalling.

Genome-wide meta-analysis associates GPSM1 with type 2 diabetes, a plausible gene involved in skeletal muscle function

2020 ◽  
Vol 65 (4) ◽  
pp. 411-420
Author(s):  
Qiuju Ding ◽  
Amelia Li Min Tan ◽  
E. J. Parra ◽  
Miguel Cruz ◽  
Xueling Sim ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Skeletal Muscle ◽  
Muscle Function ◽  
Meta Analysis ◽  
Skeletal Muscle Function ◽  
Genome Wide

Exercise Capacity Is Limited In Diabetic Mice Due To The Impairment Of Skeletal Muscle Function

2007 ◽  
Vol 39 (Supplement) ◽  
pp. S360
Author(s):  
Takashi Yokota ◽  
Shintaro Kinugawa ◽  
Syoji Matsushima ◽  
Naoki Inoue ◽  
Yukihiro Ohta ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Exercise Capacity ◽  
Muscle Function ◽  
Diabetic Mice ◽  
Skeletal Muscle Function

scholarly journals Low-Level Laser Therapy (904 nm) Counteracts Motor Deficit of Mice Hind Limb following Skeletal Muscle Injury Caused by Snakebite-Mimicking Intramuscular Venom Injection

PLoS ONE ◽  
2016 ◽  
Vol 11 (7) ◽  
pp. e0158980 ◽  
Author(s):  
Willians Fernando Vieira ◽  
Bruno Kenzo-Kagawa ◽  
José Carlos Cogo ◽  
Vitor Baranauskas ◽  
Maria Alice da Cruz-Höfling
Keyword(s):  
Skeletal Muscle ◽  
Laser Therapy ◽  
Muscle Injury ◽  
Hind Limb ◽  
Low Level Laser Therapy ◽  
Motor Deficit ◽  
Skeletal Muscle Injury ◽  
Low Level ◽  
Low Level Laser ◽  
Level Laser

Anti-inflammatory interventions and skeletal muscle injury: benefit or detriment?

2013 ◽  
Vol 115 (6) ◽  
pp. 920-928 ◽  
Author(s):  
Maria L. Urso
Keyword(s):  
Skeletal Muscle ◽  
Inflammatory Response ◽  
Muscle Injury ◽  
Treatment Options ◽  
Current Treatment ◽  
Negative Effects ◽  
Skeletal Muscle Function ◽  
Skeletal Muscle Injury ◽  
Inflammatory Processes ◽  
Anti Inflammatory

Exercise, eccentric contractions, acute trauma, and disease are all causal mechanisms of skeletal muscle injury. After skeletal muscle is injured, it undergoes sequential phases of degeneration, inflammation, regeneration, and fibrosis. Events that occur in response to inflammation trigger regenerative processes. However, since inflammation causes pain, decreases skeletal muscle function, has a negative effect on performance, and contributes to fibrosis, which is one of the leading causes of delayed regeneration, the general practice has been to reduce inflammation. The problem with this approach is that preventing inflammation may hinder recovery. Current treatment options for inflammation are not necessarily effective and, in some cases, they may be unsafe. This review focuses on the question of whether the most beneficial course of treatment should be to block inflammation or if it is sensible to allow inflammatory processes to progress naturally. If blocking inflammation is perceived as a beneficial approach, it is not yet known at what time point during the inflammatory response it is most sensible to interfere. To address these issues, this review evaluates the effects of various anti-inflammatory agents on recovery processes in response to exercise-induced, traumatic, and disease-associated models of skeletal muscle injury. A collective analysis such as this should lay the foundation for future work that systematically manipulates the inflammatory response to most effectively promote regeneration and functional recovery in injured skeletal muscle, while reducing the negative effects of inflammatory processes such as pain and fibrosis.

scholarly journals Type 2 diabetes does not account for ethnic differences in exercise capacity or skeletal muscle function in older adults

Diabetologia ◽  
2019 ◽  
Vol 63 (3) ◽  
pp. 624-635
Author(s):  
Siana Jones ◽  
Therese Tillin ◽  
Suzanne Williams ◽  
Sophie V. Eastwood ◽  
Alun D. Hughes ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Skeletal Muscle ◽  
Oxygen Consumption ◽  
Grip Strength ◽  
Exercise Capacity ◽  
Ethnic Differences ◽  
Muscle Function ◽  
South Asians ◽  
Oxidative Capacity

Abstract Aims/hypothesis The aim of this study was to compare exercise capacity, strength and skeletal muscle perfusion during exercise, and oxidative capacity between South Asians, African Caribbeans and Europeans, and determine what effect ethnic differences in the prevalence of type 2 diabetes has on these functional outcomes. Methods In total, 708 participants (aged [mean±SD] 73 ± 7 years, 56% male) were recruited from the Southall and Brent Revisited (SABRE) study, a UK population-based cohort comprised of Europeans (n = 311) and South Asian (n = 232) and African Caribbean (n = 165) migrants. Measurements of exercise capacity using a 6 min stepper test (6MST), including measurement of oxygen consumption ($$ \dot{V}{\mathrm{O}}_2 $$V̇O2) and grip strength, were performed. Skeletal muscle was assessed using near infrared spectroscopy (NIRS); measures included changes in tissue saturation index (∆TSI%) with exercise and oxidative capacity (muscle oxygen consumption recovery, represented by a time constant [τ]). Analysis was by multiple linear regression. Results When adjusted for age and sex, in South Asians and African Caribbeans, exercise capacity was reduced compared with Europeans ($$ \dot{V}{\mathrm{O}}_2 $$V̇O2 [ml min−1 kg−1]: β = −1.2 [95% CI –1.9, −0.4], p = 0.002, and β −1.7 [95% CI –2.5, −0.8], p < 0.001, respectively). South Asians had lower and African Caribbeans had higher strength compared with Europeans (strength [kPa]: β = −9 [95% CI –12, −6), p < 0.001, and β = 6 [95% CI 3, 9], p < 0.001, respectively). South Asians had greater decreases in TSI% and longer τ compared with Europeans (∆TSI% [%]: β = −0.9 [95% CI –1.7, −0.1), p = 0.024; τ [s]: β = 11 [95% CI 3, 18], p = 0.006). Ethnic differences in $$ \dot{V}{\mathrm{O}}_2 $$V̇O2 and grip strength remained despite adjustment for type 2 diabetes or HbA1c (and fat-free mass for grip strength). However, the differences between Europeans and South Asians were no longer statistically significant after adjustment for other possible mediators or confounders (including physical activity, waist-to-hip ratio, cardiovascular disease or hypertension, smoking, haemoglobin levels or β-blocker use). The difference in ∆TSI% between Europeans and South Asians was marginally attenuated after adjustment for type 2 diabetes or HbA1c and was also no longer statistically significant after adjusting for other confounders; however, τ remained significantly longer in South Asians vs Europeans despite adjustment for all confounders. Conclusions/interpretation Reduced exercise capacity in South Asians and African Caribbeans is unexplained by higher rates of type 2 diabetes. Poorer exercise tolerance in these populations, and impaired muscle function and perfusion in South Asians, may contribute to the higher morbidity burden of UK ethnic minority groups in older age.

scholarly journals An endocrine-hepato-muscular metabolic cycle links skeletal muscle atrophy and hyperglycemia in type 2 diabetes

2020 ◽  
Author(s):  
Jürgen G. Okun ◽  
Patricia M. Rusu ◽  
Andrea Y. Chan ◽  
Yann W. Yap ◽  
Thomas Sharkie ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Skeletal Muscle ◽  
Muscle Atrophy ◽  
Ex Vivo ◽  
Muscle Protein ◽  
Muscle Protein Synthesis ◽  
Skeletal Muscle Atrophy ◽  
Diabetic Mice ◽  
Metabolic Cycle

AbstractBoth obesity and sarcopenia are frequently associated in ageing, and together may promote the progression of related conditions such as diabetes and frailty. However, little is known about the pathophysiological mechanisms underpinning this association. Here we uncover dysregulated systemic alanine metabolism and hyper-expression of the alanine transaminases (ALT) in the liver of obese/diabetic mice and humans. Hepatocyte-selective silencing of both ALT enzymes revealed a clear role in systemic alanine clearance which related to glycemic control. In obese/diabetic mice, not only did silencing both ALT enzymes retard hyperglycemia, but also reversed skeletal muscle atrophy. This was due to a rescue of depressed skeletal muscle protein synthesis, with a liver-skeletal muscle amino acid metabolic crosstalk exemplified by ex vivo experiments. Mechanistically, chronic liver glucocorticoid and glucagon signaling driven liver alanine catabolism promoted hyperglycemia and skeletal muscle wasting. Taken together, here we reveal an endocrine-hepato-muscular metabolic cycle linking hyperglycemia and skeletal muscle atrophy in type 2 diabetes.

scholarly journals Maintenance of type 2 glycolytic myofibers with age by Mib1-Actn3 axis

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Ji-Yun Seo ◽  
Jong-Seol Kang ◽  
Ye Lynne Kim ◽  
Young-Woo Jo ◽  
Ji-Hoon Kim ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Muscle Atrophy ◽  
Muscle Function ◽  
Therapeutic Potential ◽  
Chronic Exercise ◽  
Skeletal Muscle Function ◽  
Age Related ◽  
Underlying Mechanisms ◽  
Exercise Induced

AbstractAge-associated muscle atrophy is a debilitating condition associated with loss of muscle mass and function with age that contributes to limitation of mobility and locomotion. However, the underlying mechanisms of how intrinsic muscle changes with age are largely unknown. Here we report that, with age, Mind bomb-1 (Mib1) plays important role in skeletal muscle maintenance via proteasomal degradation-dependent regulation of α-actinin 3 (Actn3). The disruption of Mib1 in myofibers (Mib1ΔMF) results in alteration of type 2 glycolytic myofibers, muscle atrophy, impaired muscle function, and Actn3 accumulation. After chronic exercise, Mib1ΔMF mice show muscle atrophy even at young age. However, when Actn3 level is downregulated, chronic exercise-induced muscle atrophy is ameliorated. Importantly, the Mib1 and Actn3 levels show clinical relevance in human skeletal muscles accompanied by decrease in skeletal muscle function with age. Together, these findings reveal the significance of the Mib1-Actn3 axis in skeletal muscle maintenance with age and suggest the therapeutic potential for the treatment or amelioration of age-related muscle atrophy.

Combination of Exercise Training and Diet Restriction Normalizes Limited Exercise Capacity and Impaired Skeletal Muscle Function in Diet-Induced Diabetic Mice

Endocrinology ◽  
2014 ◽  
Vol 155 (1) ◽  
pp. 68-80 ◽  
Author(s):  
Tadashi Suga ◽  
Shintaro Kinugawa ◽  
Shingo Takada ◽  
Tomoyasu Kadoguchi ◽  
Arata Fukushima ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Exercise Training ◽  
Exercise Capacity ◽  
Muscle Function ◽  
Normal Diet ◽  
Diabetic Mice ◽  
Diet Restriction ◽  
Skeletal Muscle Function

Exercise training (EX) and diet restriction (DR) are essential for effective management of obesity and insulin resistance in diabetes mellitus. However, whether these interventions ameliorate the limited exercise capacity and impaired skeletal muscle function in diabetes patients remains unexplored. Therefore, we investigated the effects of EX and/or DR on exercise capacity and skeletal muscle function in diet-induced diabetic mice. Male C57BL/6J mice that were fed a high-fat diet (HFD) for 8 weeks were randomly assigned for an additional 4 weeks to 4 groups: control, EX, DR, and EX+DR. A lean group fed with a normal diet was also studied. Obesity and insulin resistance induced by a HFD were significantly but partially improved by EX or DR and completely reversed by EX+DR. Although exercise capacity decreased significantly with HFD compared with normal diet, it partially improved with EX and DR and completely reversed with EX+DR. In parallel, the impaired mitochondrial function and enhanced oxidative stress in the skeletal muscle caused by the HFD were normalized only by EX+DR. Although obesity and insulin resistance were completely reversed by DR with an insulin-sensitizing drug or a long-term intervention, the exercise capacity and skeletal muscle function could not be normalized. Therefore, improvement in impaired skeletal muscle function, rather than obesity and insulin resistance, may be an important therapeutic target for normalization of the limited exercise capacity in diabetes. In conclusion, a comprehensive lifestyle therapy of exercise and diet normalizes the limited exercise capacity and impaired muscle function in diabetes mellitus.

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