The role of the myosin ATPase activity in adaptive thermogenesis by skeletal muscle

Resting skeletal muscle is a major contributor to adaptive thermogenesis, i.e., the thermogenesis that changes in response to exposure to cold or to overfeeding. The identification of the “furnace” that is responsible for increased heat generation in resting muscle has been the subject of a number of investigations. A new state of myosin, the super relaxed state (SRX), with a very slow ATP turnover rate has recently been observed in skeletal muscle (Stewart et al. in Proc Natl Acad Sci USA 107:430–435, 2010). Inhibition of the myosin ATPase activity in the SRX was suggested to be caused by binding of the myosin head to the core of the thick filament in a structural motif identified earlier by electron microscopy. To be compatible with the basal metabolic rate observed in vivo for resting muscle, most myosin heads would have to be in the SRX. Modulation of the population of this state, relative to the normal relaxed state, was proposed to be a major contributor to adaptive thermogenesis in resting muscle. Transfer of only 20% of myosin heads from the SRX into the normal relaxed state would cause muscle thermogenesis to double. Phosphorylation of the myosin regulatory light chain was shown to transfer myosin heads from the SRX into the relaxed state, which would increase thermogenesis. In particular, thermogenesis by myosin has been proposed to play a role in the dissipation of calories during overfeeding. Up-regulation of muscle thermogenesis by pharmaceuticals that target the SRX would provide new approaches to the treatment of obesity or high blood sugar levels

Outlier SNPs detect weak regional structure against a background of genetic homogeneity in the Eastern Rock Lobster, Sagmariasus verreauxi

Genetic differentiation is characteristically weak in marine species making assessments of population connectivity and structure difficult. However, the advent of genomic methods has increased genetic resolution, enabling studies to detect weak, but significant population differentiation within marine species. With an increasing number of studies employing high resolution genome-wide techniques, we are realising that the connectivity of marine populations is often complex and quantifying this complexity can provide an understanding of the processes shaping marine species genetic structure and to inform long-term, sustainable management strategies. This study aims to assess the genetic structure, connectivity, and local adaptation of the Eastern Rock Lobster (Sagmariasus verreauxi), which has a maximum pelagic larval duration of 12 months and inhabits both subtropical and temperate environments. We used 645 neutral and 15 outlier SNPs to genotype lobsters collected from the only two known breeding populations and a third episodic population—encompassing S. verreauxi's known range. Through examination of the neutral SNP panel, we detected genetic homogeneity across the three regions, which extended across the Tasman Sea encompassing both Australian and New Zealand populations. We discuss differences in neutral genetic signature of S. verreauxi and a closely related, co-distributed rock lobster, Jasus edwardsii, determining a regional pattern of genetic disparity between the species, which have largely similar life histories. Examination of the outlier SNP panel detected weak genetic differentiation between the three regions. Outlier SNPs showed promise in assigning individuals to their sampling origin and may prove useful as a management tool for species exhibiting genetic homogeneity

Magnetic susceptibility anisotropy of myocardium imaged by cardiovascular magnetic resonance reflects the anisotropy of myocardial filament α-helix polypeptide bonds

BACKGROUND: A key component of evaluating myocardial tissue function is the assessment of myofiber organization and structure. Studies suggest that striated muscle fibers are magnetically anisotropic, which, if measurable in the heart, may provide a tool to assess myocardial microstructure and function. METHODS: To determine whether this weak anisotropy is observable and spatially quantifiable with cardiovascular magnetic resonance (CMR), both gradient-echo and diffusion-weighted data were collected from intact mouse heart specimens at 9.4 Tesla. Susceptibility anisotropy was experimentally calculated using a voxelwise analysis of myocardial tissue susceptibility as a function of myofiber angle. A myocardial tissue simulation was developed to evaluate the role of the known diamagnetic anisotropy of the peptide bond in the observed susceptibility contrast. RESULTS: The CMR data revealed that myocardial tissue fibers that were parallel and perpendicular to the magnetic field direction appeared relatively paramagnetic and diamagnetic, respectively. A linear relationship was found between the magnetic susceptibility of the myocardial tissue and the squared sine of the myofiber angle with respect to the field direction. The multi-filament model simulation yielded susceptibility anisotropy values that reflected those found in the experimental data, and were consistent that this anisotropy decreased as the echo time increased. CONCLUSIONS: Though other sources of susceptibility anisotropy in myocardium may exist, the arrangement of peptide bonds in the myofilaments is a significant, and likely the most dominant source of susceptibility anisotropy. This anisotropy can be further exploited to probe the integrity and organization of myofibers in both healthy and diseased heart tissue

Atomic model of the human cardiac muscle myosin filament

Of all the myosin filaments in muscle, the most important in terms of human health, and so far the least studied, are those in the human heart. Here we report a 3D single-particle analysis of electron micrograph images of negatively stained myosin filaments isolated from human cardiac muscle in the normal (undiseased) relaxed state. The resulting 28-angstrom resolution 3D reconstruction shows axial and azimuthal (no radial) myosin head perturbations within the 429-angstrom axial repeat, with rotations between successive 132 angstrom-, 148 angstrom-, and 149 angstrom-spaced crowns of heads close to 60 degrees, 35 degrees, and 25 degrees (all would be 40 degrees in an unperturbed three-stranded helix). We have defined the myosin head atomic arrangements within the three crown levels and have modeled the organization of myosin subfragment 2 and the possible locations of the 39 angstrom-spaced domains of titin and the cardiac isoform of myosin-binding protein-C on the surface of the myosin filament backbone. Best fits were obtained with head conformations on all crowns close to the structure of the two-headed myosin molecule of vertebrate chicken smooth muscle in the dephosphorylated relaxed state. Individual crowns show differences in head-pair tilts and subfragment 2 orientations, which, together with the observed perturbations, result in different intercrown head interactions, including one not reported before. Analysis of the interactions between the myosin heads, the cardiac isoform of myosin-binding protein-C, and titin will aid in understanding of the structural effects of mutations in these proteins known to be associated with human cardiomyopathies