Richard W.A. Mackenzie

The central role of myostatin in skeletal muscle and whole body homeostasis

Myostatin is a powerful negative regulator of skeletal muscle mass in mammalian species. It plays a key role in skeletal muscle homeostasis and has now been well described since its discovery. Myostatin is capable of inducing muscle atrophy via its inhibition of myoblast proliferation, increasing ubiquitin‐proteasomal activity and downregulating activity of the IGF–Akt pathway. These well‐recognized effects are seen in multiple atrophy causing situations, including injury, diseases such as cachexia, disuse and space flight, demonstrating the importance of the myostatin signalling mechanism. Based on this central role, significant work has been pursued to inhibit myostatins actions in vivo. Importantly, several new studies have uncovered roles for myostatin distinct from skeletal muscle size. Myostatin has been suggested to play a role in cardiomyocyte homeostasis, glucose metabolism and adipocyte proliferation, all of which are examined in detail below. Based on these effects, myostatin inhibition has potential to be widely utilized in many Western diseases such as chronic obstructive pulmonary disease, type II diabetes and obesity. However, if myostatin inhibitors are to successfully translate from bench‐top to bedside in the near future, awareness must be raised on these non‐traditional effects of myostatin away from skeletal muscle. Indeed, further research into these novel areas is required.

Akt/PKB activation and insulin signaling: a novel insulin signaling pathway in the treatment of type 2 diabetes.

Type 2 diabetes is a metabolic disease categorized primarily by reduced insulin sensitivity, β-cell dysfunction, and elevated hepatic glucose production. Treatments reducing hyperglycemia and the secondary complications that result from these dysfunctions are being sought after. Two distinct pathways encourage glucose transport activity in skeletal muscle, ie, the contraction-stimulated pathway reliant on Ca2+/5′-monophosphate-activated protein kinase (AMPK)-dependent mechanisms and an insulin-dependent pathway activated via upregulation of serine/threonine protein kinase Akt/PKB. Metformin is an established treatment for type 2 diabetes due to its ability to increase peripheral glucose uptake while reducing hepatic glucose production in an AMPK-dependent manner. Peripheral insulin action is reduced in type 2 diabetics whereas AMPK signaling remains largely intact. This paper firstly reviews AMPK and its role in glucose uptake and then focuses on a novel mechanism known to operate via an insulin-dependent pathway. Inositol hexakisphosphate (IP6) kinase 1 (IP6K1) produces a pyrophosphate group at the position of IP6 to generate a further inositol pyrophosphate, ie, diphosphoinositol pentakisphosphate (IP7). IP7 binds with Akt/PKB at its pleckstrin homology domain, preventing interaction with phosphatidylinositol 3,4,5-trisphosphate, and therefore reducing Akt/PKB membrane translocation and insulin-stimulated glucose uptake. Novel evidence suggesting a reduction in IP7 production via IP6K1 inhibition represents an exciting therapeutic avenue in the treatment of insulin resistance. Metformin-induced activation of AMPK is a key current intervention in the management of type 2 diabetes. However, this treatment does not seem to improve peripheral insulin resistance. In light of this evidence, we suggest that inhibition of IP6K1 may increase insulin sensitivity and provide a novel research direction in the treatment of insulin resistance.

Acute hypoxia and exercise improve insulin sensitivity (SI2*) in individuals with type 2 diabetes

Hypoxia has been shown to increase glucose uptake in skeletal muscle using the contraction‐stimulated pathway, independent of the actions of insulin. Yet, the same stress has also been linked with causing insulin resistance and hyperglycaemia. The aim of this study was to examine the effects of acute hypoxia with and without exercise on insulin sensitivity (

Concurrent resistance and aerobic exercise stimulates both myofibrillar and mitochondrial protein synthesis in sedentary middle-aged men

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Heat acclimation improves intermittent sprinting in the heat but additional pre-cooling offers no further ergogenic effect

) in individuals with type 2 diabetes.

Intermittent exercise with and without hypoxia improves insulin sensitivity in individuals with Type 2 diabetes

We determined myofibrillar and mitochondrial protein fractional synthesis rates (FSR), intramuscular signaling protein phosphorylation, and mRNA expression responses after isolated bouts of resistance exercise (RE), aerobic exercise (AE), or in combination [termed concurrent exercise (CE)] in sedentary middle-aged men. Eight subjects (age = 53.3 ± 1.8 yr; body mass index = 29.4 ± 1.4 kg·m(2)) randomly completed 8 × 8 leg extension repetitions at 70% of one repetition-maximum, 40 min of cycling at 55% peak aerobic power output (AE), or (consecutively) 50% of the RE and AE trials (CE). Biopsies were obtained (during a primed, constant infusion of l-[ring-(13)C(6)]phenylalanine) while fasted, and at 1 and 4 h following postexercise ingestion of 20 g of protein. All trials increased mitochondrial FSR above fasted rates (RE = 1.3-fold; AE = 1.5; CE = 1.4; P < 0.05), although only CE (2.2) and RE (1.8) increased myofibrillar FSR (P < 0.05). At 1 h postexercise, phosphorylation of Akt on Ser(473) (CE = 7.7; RE = 4.6) and Thr(308) (CE = 4.4; RE = 2.9), and PRAS40 on Thr(246) (CE = 3.8; AE = 2.5) increased (P < 0.05), with CE greater than AE for Akt Ser(473)-Thr(308) and greater than RE for PRAS40 (P < 0.05). Despite increased phosphorylation of Akt-PRAS40, phosphorylation of mammalian target of rapamycin (Ser(2448)) remained unchanged (P > 0.05), while rpS6 (Ser(235/236)) increased only in RE (10.4) (P < 0.05). CE and AE both resulted in increased peroxisome proliferator receptor-γ coactivator 1-α (PGC1α) expression at 1 h (CE = 2.9; AE = 2.8; P < 0.05) and 4 h (CE = 2.6; AE = 2.4) and PGC1β expression at 4 h (CE = 2.1; AE = 2.6; P < 0.05). These data suggest that CE-induced acute stimulation of myofibrillar and mitochondrial FSR, protein signaling, and mRNA expression are equivalent to either isolate mode (RE or AE). These results occurred without an interference effect on muscle protein subfractional synthesis rates, protein signaling, or mRNA expression.

Attenuation of plasma annexin A1 in human obesity

Abstract The aim of this study was to determine the effect of 10 days of heat acclimation with and without pre-cooling on intermittent sprint exercise performance in the heat. Eight males completed three intermittent cycling sprint protocols before and after 10 days of heat acclimation. Before acclimation, one sprint protocol was conducted in control conditions (21.8 ± 2.2°C, 42.8 ± 6.7% relative humidity) and two sprint protocols in hot, humid conditions (33.3 ± 0.6°C, 52.2 ± 6.8% relative humidity) in a randomized order. One hot, humid condition was preceded by 20 min of thigh pre-cooling with ice packs (−16.2 ± 4.5°C). After heat acclimation, the two hot, humid sprint protocols were repeated. Before heat acclimation, peak power output declined in the heat (P < 0.05) but pre-cooling prevented this. Ten days of heat acclimation reduced resting rectal temperature from 37.8 ± 0.3°C to 37.4 ± 0.3°C (P < 0.01). When acclimated, peak power output increased by ∼2% (P < 0.05, main effect) and no reductions in individual sprint peak power output were observed. Additional pre-cooling offered no further ergogenic effect. Unacclimated athletes competing in the heat should pre-cool to prevent reductions in peak power output, but heat acclimate for an increased peak power output.

The Effect of Hypoxia and Work Intensity on Insulin Resistance in Type 2 Diabetes

CONTEXT Hypoxia and muscle contraction stimulate glucose transport activity in vitro. Exercise and hypoxia have additive effects on insulin sensitivity in type 2 diabetics (T2D). OBJECTIVE The objective of the study was to examine the effectiveness of intermittent exercise with and without hypoxia on acute- and moderate-term glucose kinetics and insulin sensitivity in T2D. SETTING The study was conducted at a university research center. DESIGN, PARTICIPANTS, AND INTERVENTIONS Eight male T2D patients completed the following: 1) 60 min of continuous exercise at 90% lactate threshold in hypoxia (HyEx60); 2) intermittent exercise at 120% lactate threshold, separated by periods of passive recovery (5:5 min) in hypoxia [Hy5:5; O₂ ∼ 14.7 (0.2)%]; and 3) intermittent exercise (5:5 min) at 120% lactate threshold in normoxia (O₂ ∼ 20.93%). MAIN OUTCOME MEASURES Glucose appearance and glucose disappearance, using an adapted non-steady-state one-compartment model were measured. Homeostasis models of insulin resistance (HOMA(IR)), fasting insulin resistance index (FIRI), and β-cell function were calculated 24 and 48 h after exercise conditions. RESULTS Glucose disappearance increased from baseline (1.85 mg/kg · min⁻¹) compared with 24 h (2.01 min/kg · min⁻¹) after HyEx60 (P = 0.031). No difference was noted for both Hy5:5 (P = 0.064) and normoxia (P = 0.385). Hy5:5 demonstrated improvements in HOMA(IR) from baseline [d 1, 6.20 (0.40)] when comparisons were made with d 2 [4.83 (0.41)] (P = 0.0013). HOMA(IR) and FIRI improved in the 24 h (HOMA(IR), P = 0.002; FIRI, P = 0.003), remaining reduced 48 h after HyEx60 (HOMA(IR), P = 0.028; and FIRI, P = 0.034). CONCLUSION HyEx60 offered the greatest improvements in acute and moderate-term glucose control in T2D. Intermittent exercise stimulated glucose disposal and improved post-exercise insulin resistance, which was enhanced when exercise was combined with hypoxia (Hy5:5). The data suggest a use of hypoxic exercise in treatment of T2D.

Human monocyte heat shock protein 72 responses to acute hypoxic exercise after 3 days of exercise heat acclimation

Obesity‐related metabolic disorders are characterized by mild chronic inflammation, leukocyte infiltration, and tissue fibrosis as a result of adipocytokine production from the expanding white adipose tissue. Annexin A1 (AnxA1) is an endogenous glucocorticoid regulated protein, which modulates systemic anti‐inflammatory processes and, therefore, may be altered with increasing adiposity in humans. Paradoxically, we found that plasma AnxA1 concentrations inversely correlated with BMI, total percentage body fat, and waist‐to‐hip ratio in human subjects. Plasma AnxA1 was also inversely correlated with plasma concentrations of the acute‐phase protein, C‐reactive protein (CRP), and the adipocytokine leptin, suggesting that as systemic inflammation increases, anti‐inflammatory AnxA1 is reduced. In addition, AnxA1 gene expression and protein were significantly up‐regulated during adipogenesis in a human adipocyte cell line compared to vehicle alone, demonstrating for the first time that AnxA1 is expressed and excreted from human adipocytes. These data demonstrate a failure in the endogenous anti‐inflammatory system to respond to increasing systemic inflammation resulting from expanding adipose tissue, a condition strongly linked to the development of type 2 diabetes and cardiovascular disease. These data raise the possibility that a reduction in plasma AnxA1 may contribute to the chronic inflammatory phenotype observed in human obesity.—Kosicka, A., Cunliffe, A. D., Mackenzie, R., Gulrez Zariwala, M., Perretti, M., Flower, R. J., Renshaw, D. Attenuation of plasma annexin A1 in human obesity. FASEB J. 27, 368–378 (2013). www.fasebj.org

A Molecular and Whole Body Insight of the Mechanisms Surrounding Glucose Disposal and Insulin Resistance with Hypoxic Treatment in Skeletal Muscle.

CONTEXT Hypoxia and muscle contraction stimulate glucose transport in vitro. We have previously demonstrated that exercise and hypoxia have an additive effect on insulin sensitivity in type 2 diabetics. OBJECTIVES Our objective was to examine the effects of three different hypoxic/exercise (Hy Ex) trials on glucose metabolism and insulin resistance in the 48 h after acute hypoxia in type 2 diabetics. DESIGN, PARTICIPANTS, AND INTERVENTIONS Eight male type 2 diabetics completed 60 min of hypoxic [mean (sem) O(2) = ∼14.7 (0.2)%] exercise at 90% of lactate threshold [Hy Ex(60); 49 (1) W]. Patients completed an additional two hypoxic trials of equal work, lasting 40 min [Hy Ex(40); 70 (1) W] and 20 min [Hy Ex(20); 140 (12) W]. MAIN OUTCOME MEASURES Glucose rate of appearance and rate of disappearance were determined using the one-compartment minimal model. Homeostasis models of insulin resistance (HOMA(IR)), fasting insulin resistance index and β-cell function (HOMA(β-cell)) were calculated at 24 and 48 h after trials. RESULTS Peak glucose rate of appearance was highest during Hy Ex(20) [8.89 (0.56) mg/kg · min, P < 0.05]. HOMA(IR) and fasting insulin resistance index were improved in the 24 and 48 h after Hy Ex(60) and Hy Ex(40) (P < 0.05). HOMA(IR) decreased 24 h after Hy Ex(20) (P < 0.05) and returned to baseline values at 48 h. CONCLUSIONS Moderate-intensity exercise in hypoxia (Hy Ex(60) and Hy Ex(40)) stimulates acute- and moderate-term improvements in insulin sensitivity that were less apparent in Hy Ex(20). Results suggest that exercise duration and not total work completed has a greater influence on acute and moderate-term glucose control in type 2 diabetics.