Aging is associated with insulin resistance and the development of type 2 diabetes. While this process is multifaceted, age-related changes to skeletal muscle are expected to contribute to impaired ...glucose metabolism. Some of these changes include sarcopenia, impaired insulin signaling, and imbalances in glucose utilization. Endurance and resistance exercise training have been endorsed as interventions to improve glucose tolerance and whole-body insulin sensitivity in the elderly. While both types of exercise generally increase insulin sensitivity in older adults, the metabolic pathways through which this occurs can differ and can be dependent on preexisting conditions including obesity and type 2 diabetes. In this review, we will first highlight age-related changes to skeletal muscle which can contribute to insulin resistance, followed by a comparison of endurance and resistance training adaptations to insulin-stimulated glucose metabolism in older adults.
The age-related loss of skeletal muscle (sarcopenia) is a major health concern as it is associated with physical disability, metabolic impairments, and increased mortality. The coexistence of ...sarcopenia with obesity, termed 'sarcopenic obesity', contributes to skeletal muscle insulin resistance and the development of type 2 diabetes, a disease prevalent with advancing age. Despite this knowledge, the mechanisms contributing to sarcopenic obesity remain poorly understood, preventing the development of targeted therapeutics. This article will discuss the clinical and physiological consequences of sarcopenic obesity and propose myostatin as a potential candidate contributing to this condition. A special emphasis will be placed on examining the role of myostatin signaling in impairing both skeletal muscle growth and insulin signaling. In addition, the role of myostatin in regulating muscle-to fat cross talk, further exacerbating metabolic dysfunction in the elderly, will be highlighted. Lastly, we discuss how this knowledge has implications for the design of myostatin-inhibitor clinical trials.
Elevated circulating lactate has been associated with obesity and insulin resistance. The aim of the current study was to determine if lactate-induced lysine lactylation (kla), a post-translational ...modification, was present in human skeletal muscle and related to insulin resistance. Fifteen lean (Body Mass Index: 22.1 ± 0.5 kg/m
) and fourteen obese (40.6 ± 1.4 kg/m
) adults underwent a muscle biopsy and 2-h oral glucose tolerance test. Skeletal muscle lactylation was increased in obese compared to lean females (19%,
< 0.05) and associated with insulin resistance (r = 0.37,
< 0.05) in the whole group. Skeletal muscle lactylation levels were significantly associated with markers of anaerobic metabolism (plasma lactate and skeletal muscle lactate dehydrogenase LDH,
< 0.05) and negatively associated with markers of oxidative metabolism (skeletal muscle cytochrome c oxidase subunit 4 and Complex I pyruvate OXPHOS capacity,
< 0.05). Treatment of primary human skeletal muscle cells (HSkMC) with sodium lactate for 24 h increased protein lactylation and IRS-1 serine 636 phosphorylation in a similar dose-dependent manner (
< 0.05). Inhibition of glycolysis (with 2-deoxy-d-glucose) or LDH-A (with sodium oxamate or LDH-A siRNA) for 24 h reduced HSkMC lactylation which paralleled reductions in culture media lactate accumulation. This study identified the existence of a lactate-derived post-translational modification in human skeletal muscle and suggests skeletal muscle lactylation could provide additional insight into the regulation of skeletal muscle metabolism, including insulin resistance.
The purpose of this study was to determine whether plasma lactate and skeletal muscle glucose regulatory pathways, specifically PDH dephosphorylation, are impaired during hyperinsulinemic conditions ...in middle- to older-aged individuals and determine whether exercise training could improve key variables responsible for skeletal muscle PDH regulation. Eighteen young (19-29 yr; n = 9 males and 9 females) and 20 middle- to older-aged (57-82 yr; n = 10 males and 10 females) individuals underwent a 2-h euglycemic hyperinsulinemic clamp. Plasma samples were obtained at baseline and at 30, 50, 90, and 120 min for analysis of lactate, and skeletal muscle biopsies were performed at 60 min for analysis of protein associated with glucose metabolism. In response to insulin, plasma lactate was elevated in aged individuals when normalized to insulin action. Insulin-stimulated phosphorylation of skeletal muscle PDH on serine sites 232, 293, and 300 decreased in young individuals only. Changes in insulin-stimulated PDH phosphorylation were positively related to changes in plasma lactate. No age-related differences were observed in skeletal muscle phosphorylation of LDH, GSK-3α, or GSK-3β in response to insulin or PDP1, PDP2, PDK2, PDK4, or MPC1 total protein. Twelve weeks of endurance- or strength-oriented exercise training improved insulin-stimulated PDH dephosphorylation, which was related to a reduced lactate response. These findings suggest that impairments in insulin-induced PDH regulation in a sedentary aging population contribute to impaired glucose metabolism and that exercise training is an effective intervention for treating metabolic inflexibility.
The purpose of the present study was to determine the effects of obesity and biological sex on myostatin expression in humans and to examine the direct effects of myostatin, SMAD2, and SMAD3 on ...insulin signaling in primary human skeletal muscle cells (HSkMCs). For
, 15 lean body mass index (BMI): 22.1 ± 0.5 kg/m
;
= 8 males;
= 7 females and 14 obese (BMI: 40.6 ± 1.4 kg/m
;
= 7 males;
= 7 females) individuals underwent skeletal muscle biopsies and an oral glucose tolerance test. For
, 14 young lean (BMI: 22.4 ± 1.9 kg/m
;
= 6 males;
= 8 females) and 14 obese (BMI: 39.3 ± 7.9 kg/m
;
= 6 males;
= 8 females) individuals underwent muscle biopsies for primary HSkMC experiments. Plasma mature myostatin (
= 0.041), skeletal muscle precursor myostatin (
= 0.048), and skeletal muscle SMAD3 (
= 0.029) were elevated in obese females compared to lean females, and plasma mature myostatin (
= 0.58,
= 0.029) and skeletal muscle SMAD3 (
= 0.56,
= 0.037) were associated with insulin resistance in females but not males. Twenty-four hours of myostatin treatment impaired insulin signaling in primary HSkMCs derived from females (
< 0.024) but not males. Overexpression of SMAD3, but not SMAD2, impaired insulin-stimulated AS160 phosphorylation in HSkMCs derived from lean females (-27%,
= 0.040), whereas silencing SMAD3 improved insulin-stimulated AS160 phosphorylation and insulin-stimulated glucose uptake (25%,
< 0.014) in HSkMCs derived from obese females. These results suggest for the first time that myostatin-induced impairments in skeletal muscle insulin signaling are sex specific and that increased body fat in females is associated with detrimental elevations in myostatin and SMAD3, which contribute to obesity-related insulin resistance.
Obesity is considered a main risk factor for the development of insulin resistance and type 2 diabetes. The present study utilizes in vivo and in vitro experiments in human skeletal muscle to demonstrate for the first time that females are inherently more susceptible to myostatin-induced insulin resistance, which is further enhanced with obesity due to increased myostatin and SMAD3 expression.
Summary
Objective
The high molecular weight (HMW) adiponectin isoform is considered the active form of adiponectin and is linked to insulin sensitivity and the reduced risk of developing ...cardiovascular disease. The purpose of the first study was to determine the effects of age and sex on the plasma HMW adiponectin response to acute hyperinsulinemia, and secondly determine whether either endurance or resistance exercise training could affect this response.
Design and Participants
Twenty‐six healthy males (19‐84 years) and twenty‐six healthy females (18‐76 years) were recruited and matched for BMI to examine the effects of sex and age on the plasma adiponectin response to a 2‐hour hyperinsulinemic‐euglycemic clamp. To examine the effects of exercise training, a subgroup of young (<35 years) and aged (>55 years) individuals were randomized into a 12‐week endurance or resistance training programme and had their adiponectin response to hyperinsulinemia measured before and after training. High molecular weight (HMW) and total adiponectin were measured by ELISA.
Results
In response to hyperinsulinemia, plasma HMW adiponectin decreased in females (−9%, P < .005), but not males. After 12 weeks of endurance training, the response of plasma HMW adiponectin to hyperinsulinemia increased in older females (36%, P < .05) only. Resistance training had no effect on the plasma adiponectin response to hyperinsulinemia. Despite no age or sex differences at baseline, skeletal muscle AdipoR1 increased in response to endurance training (~120%, P < .001) and resistance training (~38%, P < .05), regardless of age or sex.
Conclusion
The inhibitory action of hyperinsulinemia on plasma HMW adiponectin occurs in females but not males, irrespective of age. Twelve weeks of endurance training protects older females against the hyperinsulinemic inhibition of plasma HMW adiponectin, which could promote healthy ageing.
Optimal health benefits from exercise are achieved by meeting both aerobic and muscle strengthening guidelines, however, most older adults (OAs) do not exercise and the majority of those who do only ...perform one type of exercise. A pragmatic solution to this problem may be emphasizing a single exercise strategy that maximizes health benefits. The loss of muscle mass and strength at an accelerated rate are hallmarks of aging that, without intervention, eventually lead to physical disability and loss of independence. Additionally, OAs are at risk of developing several chronic diseases. As such, participating in activities that can maintain or increase muscle mass and strength, as well as decrease chronic disease risk, is essential for healthy aging. Unfortunately, there is a widely held belief that adaptations to aerobic and resistance exercise are independent of each other, requiring the participation of both types of exercise to achieve optimal health. However, we argue that this assertion is incorrect, and we discuss crossover adaptations of both aerobic and resistance exercise. Aerobic exercise can increase muscle mass and strength, though not consistently and may be limited to exercise that overloads a particular muscle group, such as stationary bicycling. In contrast, resistance exercise is effective at maintaining muscle health with increasing age, and also has significant effects on cardiovascular disease (CVD) risk factors, type 2 diabetes (T2D), cancer, and mortality. We posit that resistance exercise is the most effective standalone exercise strategy for improving overall health in OAs and should be emphasized in future guidelines.
Aging decreases skeletal muscle mass and strength, but aerobic and resistance exercise training maintains skeletal muscle function. NAD+ is a coenzyme for ATP production and a required substrate for ...enzymes regulating cellular homeostasis. In skeletal muscle, NAD+ is mainly generated by the NAD+ salvage pathway in which nicotinamide phosphoribosyltransferase (NAMPT) is rate‐limiting. NAMPT decreases with age in human skeletal muscle, and aerobic exercise training increases NAMPT levels in young men. However, whether distinct modes of exercise training increase NAMPT levels in both young and old people is unknown. We assessed the effects of 12 weeks of aerobic and resistance exercise training on skeletal muscle abundance of NAMPT, nicotinamide riboside kinase 2 (NRK2), and nicotinamide mononucleotide adenylyltransferase (NMNAT) 1 and 3 in young (≤35 years) and older (≥55 years) individuals. NAMPT in skeletal muscle correlated negatively with age (r2 = 0.297, P < 0.001, n = 57), and VO2peak was the best predictor of NAMPT levels. Moreover, aerobic exercise training increased NAMPT abundance 12% and 28% in young and older individuals, respectively, whereas resistance exercise training increased NAMPT abundance 25% and 30% in young and in older individuals, respectively. None of the other proteins changed with exercise training. In a separate cohort of young and old people, levels of NAMPT, NRK1, and NMNAT1/2 in abdominal subcutaneous adipose tissue were not affected by either age or 6 weeks of high‐intensity interval training. Collectively, exercise training reverses the age‐dependent decline in skeletal muscle NAMPT abundance, and our findings highlight the value of exercise training in ameliorating age‐associated deterioration of skeletal muscle function.
NAMPT is crucially important for maintaining skeletal muscle NAD+ levels. We show that both endurance‐ and resistance‐type exercise training reverses the age‐dependent decline in skeletal muscle NAMPT abundance. Our findings highlight the value of exercise training in ameliorating age‐associated deterioration of skeletal muscle function.
Wnt5a is a highly studied member of the Wnt family and recently has been implicated in the pathogenesis of atherosclerosis, but its precise role is unknown. Foam cell development is a critical ...process to atherosclerotic plaque formation. In the present study, we investigated the role of noncanonical Wnt5a signaling in the development of foam cells.
Human carotid atherosclerotic tissue and THP-1-derived macrophages were used to investigate the contribution of Wnt5a signaling in the formation of foam cells. Immunohistochemistry was used to evaluate protein expression of scavenger receptors and noncanonical Wnt5a receptors frizzled 5 (Fz5) and receptor tyrosine kinase-like orphan receptor 2 (Ror2) in human atherosclerotic macrophages/foam cells. Changes in protein expression in response to Wnt5a stimulation/inhibition were determined by Western blot, and lipid accumulation was evaluated by fluorescent lipid droplet staining.
Wnt5a (P<.05), Fz5 (P<.01), and Ror2 (P<.01) were significantly expressed in advanced atherosclerotic lesions compared to less advanced lesions (N=10). Wnt5a, Fz5, and Ror2 were expressed in macrophages/foam cells within the plaque. In vitro studies revealed that Wnt5a significantly increased the expression of the lipid uptake receptor CD36 (P<.05) but not the lipid efflux receptor ATP-binding cassette transporter (P>.05). rWnt5a also significantly increased lipid accumulation in THP-1 macrophages (P<.05). Furthermore, inhibition of Wnt5a signaling with Box5 prevented lipid accumulation (P<.01) and prevented CD36 up-regulation (P<.01).
These results suggest a direct role for Wnt5a signaling in the pathogenesis of atherosclerosis, specifically the accumulation of lipid in macrophages and the formation of foam cells.
•Noncanonical Wnt5a receptors, Fz5 and Ror2, are expressed in atherosclerosis.•Wnt5a regulates CD36 expression and lipid accumulation in macrophages.•Wnt5a is an important player in initiation of foam cell development.•Blocking Wnt5a/Fz5 signaling is sufficient to prevent foam cell formation.•Wnt5a signaling is an attractive therapeutic to target in atherosclerosis.
PDF
