Skeletal muscle fibre plasticity in response to selected environmental and physiological stimuli

Skeletal muscle constitutes a highly adaptable and malleable tissue that responds to environmental and physiological challenges by changing its phenotype in terms of size and composition, outcomes that are brought about by changes in gene expression, biochemical and metabolic properties. Both the short- and long-term effects of nutritional alterations on skeletal muscle homeostasis have been defined as the object of intensive research over the last thirty years. This review focuses predominantly on assimilating our understanding of the changes in muscle fibre phenotype and functional properties induced by either food restriction or alternatively existing on a high fat diet. Firstly, food restriction has been shown in a number of studies to decrease the myofibre cross sectional area and consistently, it has been found that glycolytic type IIB fibres are more prone to atrophy than oxidative fibres. Secondly, in rodents, a high fat diet has been shown to induce an oxidative profile in skeletal muscle, although obese humans usually show higher numbers of glycolytic type IIB fibres. Moreover, attention is paid to the effect of prenatal maternal food restriction on muscle development of the offspring in various species. A key point related to these experiments is the timing of food restriction for the mother. Furthermore, we explore extensively the seemingly species-specific response to maternal malnutrition. Finally, key signalling molecules that play a pivotal role in energy metabolism, fibre type transitions and muscle hypertrophy are discussed in detail.

The effect of impaired thyroid function during development on the mechanical properties of avian bone

Thyroid hormones show fluctuating levels during the post-hatching development of birds. In this paper we report the results of the first mechanical tests to quantify the effect of hypothyroidism, during post-natal development, on the skeletal properties of a precocial bird, the barnacle goose, as determined by microhardness testing. The effect of hypothyroidism is tissue-specific; bone from the femora of birds is not significantly affected by induced hypothyroidism, however, there is a strong positive relationship between the levels of circulating thyroid hormones and the mechanical properties of bone from humeri. In the barnacle goose the development of the wing skeleton and musculature depends on an increase in circulating thyroid hormones and our analysis shows that, in its absence, the mechanical competence of the bone mineral itself is reduced in addition to the decreased bone length and muscle development previously reported in the literature. (C) 2004 Wiley-Liss, Inc.

Characterisation of connective tissue from the hypertrophic skeletal muscle of myostatin null mice

Myostatin is a potent inhibitor of muscle development. Genetic deletion of myostatin in mice results in muscle mass increase, with muscles often weighing three times their normal values. Contracting muscle transfers tension to skeletal elements through an elaborate connective tissue network. Therefore, the connective tissue of skeletal muscle is an integral component of the contractile apparatus. Here we examine the connective tissue architecture in myostatin null muscle. We show that the hypertrophic muscle has decreased connective tissue content compared with wild-type muscle. Secondly, we show that the hypertrophic muscle fails to show the normal increase in muscle connective tissue content during ageing. Therefore, genetic deletion of myostatin results in an increase in contractile elements but a decrease in connective tissue content. We propose a model based on the contractile profile of muscle fibres that reconciles this apparent incompatible tissue composition phenotype.

Identification and characterisation of novel genes involved in skeletal muscle hypertrophy

There is mounting evidence in support of the view that skeletal muscle hypertrophy results from the complex and coordinated interaction of numerous signalling pathways. Well characterised components integral to skeletal muscle adaptation include the transcriptional activity of the members of the myogenic regulatory factors, numerous secreted peptide growth factors, and the regenerative potential of satellite cells. Whilst studies investigating isolated components or pathways have enhanced our current understanding of skeletal muscle hypertrophy, our knowledge of how all of these components react in concert to a common stimulus remains limited. The broad aim of this thesis was to identify and characterise novel genes involved in skeletal muscle hypertrophy. We have created a customised human skeletal muscle specific microarray which contains ∼11,000 cDNA clones derived from a normalised human skeletal muscle cDNA library as well as 270 genes with known functional roles in human skeletal muscle. The first aspect of this thesis describes the production of the microarray and evaluates the robustness and reproducibility of this analytical technique. Study one aimed to use this microarray in the identification of genes that are differentially expressed during the forced differentiation of human rhabdomyosarcoma cells, an in vitro model of skeletal muscle development. Firstly using this unique model of aberrant myogenic differentiation we aimed to identify genes with previously unidentified roles in myogenesis. Secondly, the data from this study permitted the examination of the performance of the microarray in detecting differential gene expression in a biological system. We identified several new genes with potential roles in the myogenic arrest of rhabdomyosarcoma and further characterised the expression of muscle specific genes in rhabdomyosarcoma differentiation. In study two, the molecular responses of cell cycle regulators, muscle regulatory factors, and atrophy related genes were mapped in response to a single bout of resistance exercise in human skeletal muscle. We demonstrated an increased expression of MyoD, myogenin and p21, whilst the expression of myostatin was decreased. The results of this study contribute to the existing body of knowledge on the molecular regulation skeletal muscle to a hypertrophic stimulus. In study three, the muscle samples collected in study two were analysed using the human skeletal muscle specific microarray for the identification of novel genes with potential roles in the hypertrophic process. The analysis uncovered four interesting genes (TXNIP, MLP, ASB5, FLJ 38973) that have not previously been examined in human skeletal muscle in response to resistance exercise. The functions of these genes and their potential roles in skeletal muscle are discussed. In study four, the four genes identified in study three were examined in human primary skeletal muscle cell cultures during myogenic differentiation. Human primary skeletal muscle cells were derived from the vastus lateralis muscle of 8 healthy volunteers (6 males and 2 females). Cell cultures were differentiated using serum withdrawal and serum withdrawal combined with IGF-1 supplementation. Markers of the cell proliferation, cell cycle arrest and myogenic differentiation were examined to assess the effectiveness of the differentiation stimulus. Additionally, the expressions of TXNIP, MLP, ASB5 and FLJ 38973 measured in an attempt to characterise further their roles in skeletal muscle. The expression of TXNIP changed markedly in response to both differentiation stimuli, whilst the expression of the remaining genes were not altered. Therefore it was suggested that expression of these genes might be responsive to the mechanical strain or contraction induced by the resistance exercise. In order to examine whether these novel genes responded specifically to resistance type exercise, their expression was examined following a single bout of endurance exercise. The expression of TXNIP, MLP, and FLJ 38973 remained unchanged whilst ASB5 increased 30 min following the cessation of the exercise.

Nucleic acid expressed in the hypothalamus or muscle tissue in obese animals

An isolated nucleic acid molecule comprising a sequence of nucleotides encoding or complementary to a sequence encoding a molecule or derivative or homologue thereof wherein said nucleic acid molecule is expressed in a larger amount in one or both hypothalamus tissue or muscle tissue of obese animals compared to lean animals or in fed animals compared to fasted animals. Nucleic acid sequences are disclosed. It is proposed to use the expression products of such nucleic acids as modulators and/or monitors of physiological processes associated with obesity, anorexia, weight maintenance, impaired muscle development, diabetes and/or metabolic energy levels.

Nucleic acid expressed in the hypothalamus or muscle tissue in obese animals

An isolated nucleic acid molecule comprising a sequence of nucleotides encoding or complementary to a sequence encoding a molecule or derivative or homologue thereof wherein said nucleic acid molecule is expressed in a larger amount in one or both hypothalamus tissue or muscle tissue of obese animals compared to lean animals or in fed animals compared to fasted animals. Nucleic acid sequences are disclosed. It is proposed to use the expression products of such nucleic acids as modulators and/or monitors of physiological processes associated with obesity, anorexia, weight maintenance, impaired muscle development, diabetes and/or metabolic energy levels.

Nucleic acid expressed in the hypothalamus or muscle tissue in obese animals

An isolated nucleic acid molecule comprising a sequence of nucleotides encoding or complementary to a sequence encoding a molecule or derivative or homologue thereof wherein said nucleic acid molecule is expressed in a larger amount in one or both hypothalamus tissue or muscle tissue of obese animals compared to lean animals or in fed animals compared to fasted animals. Nucleic acid sequences are disclosed. It is proposed to use the expression products of such nucleic acids as modulators and/or monitors of physiological processes associated with obesity, anorexia, weight maintenance, impaired muscle development, diabetes and/or metabolic energy levels.

Nucleic acid expressed in the hypothalamus or muscle tissue in obese animals

An isolated nucleic acid molecule comprising a sequence of nucleotides encoding or complementary to a sequence encoding a molecule or derivative or homologue thereof wherein said nucleic acid molecule is expressed in a larger amount in one or both hypothalamus tissue or muscle tissue of obese animals compared to lean animals or in fed animals compared to fasted animals. Nucleic acid sequences are disclosed. It is proposed to use the expression products of such nucleic acids as modulators and/or monitors of physiological processes associated with obesity, anorexia, weight maintenance, impaired muscle development, diabetes and/or metabolic energy levels.

Nucleic acid expressed in the hypothalamus or muscle tissue in obese animals

An isolated nucleic acid molecule comprising a sequence of nucleotides encoding or complementary to a sequence encoding a molecule or derivative or homologue thereof wherein said nucleic acid molecule is expressed in a larger amount in one or both hypothalamus tissue or muscle tissue of obese animals compared to lean animals or in fed animals compared to fasted animals. Nucleic acid sequences are disclosed. It is proposed to use the expression products of such nucleic acids as modulators and/or monitors of physiological processes associated with obesity, anorexia, weight maintenance, impaired muscle development, diabetes and/or metabolic energy levels.

NUCLEIC ACID EXPRESSED IN THE HYPOTHALAMUS OR MUSCLE TISSUE IN OBESE ANIMALS

An isolated nucleic acid molecule comprising a sequence of nucleotides encoding or complimentary to a sequence encoding a molecule or derivative or homologue thereof wherein said nucleic acid molecule is expressed in a large r amount in one or both hypothalamus tissue or muscle tissue of obese animals compared to lean animals or in fed animals compared to fasted animals. Nucle ic acid sequences are disclosed. It is proposed to use the expression products of such nucleic acids as modulators and/or monitors of physiological processes associated with obesity, anorexia, weight maintenance, impaired muscle development, diabetes and/or metabolic energy levels.

Nucleic acid expressed in hypothalamus or muscle tissue in obese animals

An isolated nucleic acid molecule comprising a sequence of nucleotides encoding or complimentary to a sequence encoding a molecule or derivative or homologue thereof wherein said nucleic acid molecule is expressed in a larger amount in one or both hypothalamus tissue or muscle tissue of obese animals compared to lean animals or in fed animals compared to fasted animals. Nucleic acid sequences are disclosed. It is proposed to use the expression products of such nucleic acids as modulators and/or monitors of physiological processes associated with obesity, anorexia, weight maintenance, impaired muscle development, diabetes and/or metabolic energy levels.

NUCLEIC ACID EXPRESSED IN THE HYPOTHALAMUS OR MUSCLE TISSUE IN OBESE ANIMALS

An isolated nucleic acid molecule comprising a sequence of nucleotides encoding or complimentary to a sequence encoding a molecule or derivative or homologue thereof wherein said nucleic acid molecule is expressed in a larger amount in one or both hypothalamus tissue or muscle tissue of obese animals compared to lean animals or in fed animals compared to fasted animals. Nucleic acid sequences are disclosed. It is proposed to use the expression products of such nucleic acids as modulators and/or monitors of physiological processes associated with obesity, anorexia, weight maintenance, impaired muscle development, diabetes and/or metabolic energy levels.

NUCLEIC ACID EXPRESSED IN THE HYPOTHALAMUS OR MUSCLE TISSUE IN OBESE ANIMALS

An isolated nucleic acid molecule comprising a sequence of nucleotides encoding or complimentary to a sequence encoding a molecule or derivative or homologue thereof wherein said nucleic acid molecule is expressed in a larger amount in one or both hypothalamus tissue or muscle tissue of obese animals compared to lean animals or in fed animals compared to fasted animals. Nucleic acid sequences are disclosed. It is proposed to use the expression products of such nucleic acids as modulators and/or monitors of physiological processes associated with obesity, anorexia, weight maintenance, impaired muscle development, diabetes and/or metabolic energy levels.

Development and physiology of gastric dilation air sacculitis in Chinook salmon, Oncorhynchus tshawytscha (Walbaum)

The syndrome known as gastric dilation air sacculitis (GDAS) has previously been shown to affect Chinook salmon, Oncorhynchus tshawytscha, in seawater (SW) aquaculture. Feed and osmoregulatory stress have been implicated as potential epidemiological co-factors. The development and physiology of GDAS was investigated in SW and freshwater (FW) adapted smolts. Diet A (low-cohesion pellets) and diet B (high-cohesion pellets) were fed to both FW- and SW-adapted fish. GDAS was induced only in the SW trial on feeding diet A. Stimulated gastro-intestinal (GI) smooth muscle contractility, and fluid transport by the pyloric caeca were different in GDAS-affected fish, which also showed osmoregulatory dysfunction. Cardiac stomach (CS) smooth muscle contractility in response to acetylcholine and potassium chloride (KCl) was significantly reduced in fish fed diet A relative to controls from weeks 3–5. In contrast, maximal pyloric sphincter (PS) circular smooth muscle contraction in response to KCl was significantly elevated in fish fed diet A in weeks 4 and 5. Serum osmolality was elevated in GDAS-affected fish from week 2 of the SW trial. Fluid transport from the mucosal to serosal surface of isolated pyloric caeca was significantly reduced in weeks 3, 4 and 5 in SW fish fed diet A. Gastric evacuation from the stomach of healthy fish was shown to be significantly different when diets of low- and high-cohesion were fed. The results are consistent with the intestinal brake playing a role in the development of the disease.

The regulation and function of the striated muscle activator of rho signaling (STARS) protein

Healthy living throughout the lifespan requires continual growth and repair of cardiac, smooth, and skeletal muscle. To effectively maintain these processes muscle cells detect extracellular stress signals and efficiently transmit them to activate appropriate intracellular transcriptional programs. The striated muscle activator of Rho signaling (STARS) protein, also known as Myocyte Stress-1 (MS1) protein and Actin-binding Rho-activating protein (ABRA) is highly enriched in cardiac, skeletal, and smooth muscle. STARS binds actin, co-localizes to the sarcomere and is able to stabilize the actin cytoskeleton. By regulating actin polymerization, STARS also controls an intracellular signaling cascade that stimulates the serum response factor (SRF) transcriptional pathway; a pathway controlling genes involved in muscle cell proliferation, differentiation, and growth. Understanding the activation, transcriptional control and biological roles of STARS in cardiac, smooth, and skeletal muscle, will improve our understanding of physiological and pathophysiological muscle development and function.