AMPK-mediated transcription in skeletal muscle

Skeletal muscle phenotype plays a critical role in human performance and health, and skeletal muscle oxidative capacity is a key determinant of exercise tolerance. More recently, defective muscle oxidative metabolism has been implicated in a number of conditions associated with the metabolic syndrome, cardiovascular disease and muscle-wasting disorders. AMPK (AMP-activated protein kinase) is a critical regulator of cellular and organismal energy balance. AMPK has also emerged as a key regulator of skeletal muscle oxidative function, including metabolic enzyme expression, mitochondrial biogenesis and angiogenesis. AMPK mediates these processes primarily through alterations in gene expression. The present review examines the role of AMPK in skeletal muscle transcription and provides an overview of the known transcriptional substrates mediating the effects of AMPK on skeletal muscle phenotype.

Histone modifications and skeletal muscle metabolic gene expression

1.      Skeletal muscle oxidative function and metabolic gene expression are co-ordinately downregulated in metabolic diseases such as insulin resistance, obesity and Type 2 diabetes. Altering skeletal muscle metabolic gene expression to favour enhanced energy expenditure is considered a potential therapy to combat these diseases.

2.      Histone deacetylases (HDACs) are chromatin-remodelling enzymes that repress gene expression. It has been shown that HDAC4 and 5 co-operatively regulate a number of genes involved in various aspects of metabolism. Understanding how HDACs are regulated provides insights into the mechanisms regulating skeletal muscle metabolic gene expression.

3.      Multiple kinases control phosphorylation-dependent nuclear export of HDACs, rendering them unable to repress transcription. We have found a major role for the AMP-activated protein kinase (AMPK) in response to energetic stress, yet metabolic gene expression is maintained in the absence of AMPK activity. Preliminary evidence suggests a potential role for protein kinase D, also a Class IIa HDAC kinase, in this response.

4.      The HDACs are also regulated by ubiquitin-mediated proteasomal degradation, although the exact mediators of this process have not been identified.

5.      Because HDACs appear to be critical regulators of skeletal muscle metabolic gene expression, HDAC inhibition could be an effective therapy to treat metabolic diseases.

6.      Together, these data show that HDAC4 and 5 are critical regulators of metabolic gene expression and that understanding their regulation could provide a number of points of intervention for therapies designed to treat metabolic diseases, such as insulin resistance, obesity and Type 2 diabetes.

Impaired muscle Ca2+ and K+ regulation contribute to poor exercise performance post-lung transplantation

Lung transplant recipients (LTx) exhibit marked peripheral limitations to exercise. We investigated whether skeletal muscle Ca2+ and K+ regulation might be abnormal in eight LTx and eight healthy controls. Peak oxygen consumption and arterialized venous plasma [K+] (where brackets denote concentration) were measured during incremental exercise. Vastus lateralis muscle was biopsied at rest and analyzed for sarcoplasmic reticulum Ca2+ release, Ca2+ uptake, and Ca2+-ATPase activity rates; fiber composition; Na+-K+-ATPase (K+-stimulated 3-O-methylfluorescein phosphatase) activity and content ([3H]ouabain binding sites); as well as for [H+] and H+-buffering capacity. Peak oxygen consumption was 47% less in LTx (P < 0.05). LTx had lower Ca2+ release (34%), Ca2+ uptake (31%), and Ca2+-ATPase activity (25%) than controls (P < 0.05), despite their higher type II fiber proportion (LTx, 75.0 ± 5.8%; controls, 43.5 ± 2.1%). Muscle [H+] was elevated in LTx (P < 0.01), but buffering capacity was similar to controls. Muscle 3-O-methylfluorescein phosphatase activity was 31% higher in LTx (P < 0.05), but [3H]ouabain binding content did not differ significantly. However, during exercise, the rise in plasma [K+]-to-work ratio was 2.6-fold greater in LTx (P < 0.05), indicating impaired K+ regulation. Thus grossly subnormal muscle calcium regulation, with impaired potassium regulation, may contribute to poor muscular performance in LTx.

Skeletal muscle GLUT-4 gene and protein regulation

Twenty two, young, healthy individuals participated in three studies aiming to assess the effect of various types of physical activity - acute exercise of moderate intensity and duration, varying intensity, short-term training - on skeletal muscle GLUT-4 gene and protein expression as well as on a range of genes encoding the proteins involved in carbohydrate metabolism in skeletal muscle.

Differential gene expression in the skeletal muscle of Psammomys obesis

Focuses on discovering and investigating altered gene expression in the skeletal muscle of Psammomys obesus which is a unique model of obesity and Type II diabetes in which its development is similar to that of the human population. Defects in the skeletal muscle are pivotal to the development of Type II diabetes. Using the latest techniques in molecular biology the regulation of a number of genes was confirmed to be altered in obese or diabetic animals compared to lean. This indicates that changes to gene expression contribute to the metabolic disturbances associated with obesity and Type II diabetes.

Effect of exercise and protein on skeletal muscle inflammatory mediators

Intense exercise results in muscular inflammation. Molecular techniques were used to identify novel inflammatory proteins in human muscle. Males and females displayed different levels of exercise-induced inflammatory proteins. Interestingly, dairy protein supplements reduced these inflammatory proteins post-exercise. Increased dietary red meat consumption, with training, had no impact on muscle inflammation, although strength gain was improved.

Active recovery, training status, muscle metabolism and repeated sprint performance

This thesis found that light exercise between repeated sprints improved performance in a subsequent bout. This was attributed to a reduction in potentially fatiguing by-products within the muscle and an increased aerobic metabolism in the second sprint.

Novel gene discovery in the muscle of obese-diabetic Psammomys obesus

Metabolism in Psammomys obesis, a polygenic animal model of obesity and type 2 diabetes is associated with dysregulated nocturnal fat oxidation in diabetic animals. Furthermore, a new gene called AGT-203 has been identified. Evidence indicates that AGT-203 is involved in abnormal glucose metabolism leading to the proposition that AGT-203 is a new candidate gene for type 2 diabetes.

Creatine transporter expression in skeletal muscle

Creatine is an important molecule involved in providing energy to the body. Its major stores are in skeletal muscle. The creatine transporter protein (CreaT) mRNA is believed to be responsible for the uptake of the majority of creatine in skeletal muscle. This thesis examined factors that might have affected the expression of the creatine transporter in skeletal muscle.

Longitudinal study of children's disordered eating and muscle preoccupation

This thesis examined the role of individual factors in the development of dieting and muscal preoccupation in children. The main factor associated with these weight and shape concerns was perfectionism. It is important to identify risk factors in order to design intervention programs to decrease these behaviours in children.

Effects of vegetarianism and exercise on muscle creatine loading and gene expression

The results of this thesis indicate that vegetarianism and prior exercise can increase skeletal muscle creatine loading. The mechanisms by which these phenomena occur remain unknown but may be related to changes in the gene expression of a cellular pump within the muscle known as the "creatine transporter".

Regulation of fat oxidative genes in human skeletal muscle

The ability of skeletal muscle to adapt fat oxidation rates is important for human health. Lipid metabolism requires the involvement of many proteins encoded by their corresponding genes. This thesis demonstrates that manipulating plasma free fatty acid levels alters the expression of selected genes involved in regulating fatty acid metabolism.