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Abstract Aims Stanniocalcin‐2 (STC2) has recently been implicated in human muscle mass variability by genetic analysis. Biochemically, STC2 inhibits the proteolytic activity of the metalloproteinase PAPP‐A, which promotes muscle growth by upregulating the insulin‐like growth factor (IGF) axis. The aim was to examine if STC2 affects skeletal muscle mass and to assess how the IGF axis mediates muscle hypertrophy induced by functional overload. Methods We compared muscle mass and muscle fiber morphology between Stc2−/− (n = 21) and wild‐type (n = 15) mice. We then quantified IGF1, IGF2, IGF binding proteins −4 and −5 (IGFBP‐4, IGFBP‐5), PAPP‐A and STC2 in plantaris muscles of wild‐type mice subjected to 4‐week unilateral overload (n = 14). Results Stc2−/− mice showed up to 10% larger muscle mass compared with wild‐type mice. This increase was mediated by greater cross‐sectional area of muscle fibers. Overload increased plantaris mass and components of the IGF axis, including quantities of IGF1 (by 2.41‐fold, p = 0.0117), IGF2 (1.70‐fold, p = 0.0461), IGFBP‐4 (1.48‐fold, p = 0.0268), PAPP‐A (1.30‐fold, p = 0.0154) and STC2 (1.28‐fold, p = 0.019). Conclusion Here we provide evidence that STC2 is an inhibitor of muscle growth upregulated, along with other components of the IGF axis, during overload‐induced muscle hypertrophy.

Abstract Background The classical functions of the skeleton encompass locomotion, protection and mineral homeostasis. However, cell-specific gene deletions in the mouse and human genetic studies have identified the skeleton as a key endocrine regulator of metabolism. The bone-specific phosphatase, Phosphatase, Orphan 1 (PHOSPHO1), which is indispensable for bone mineralisation, has been recently implicated in the regulation of energy metabolism in humans, but its role in systemic metabolism remains unclear. Here, we probe the mechanism underlying metabolic regulation by analysing Phospho1 mutant mice. Results Phospho1 −/− mice exhibited improved basal glucose homeostasis and resisted high-fat-diet-induced weight gain and diabetes. The metabolic protection in Phospho1 −/− mice was manifested in the absence of altered levels of osteocalcin. Osteoblasts isolated from Phospho1 −/− mice were enriched for genes associated with energy metabolism and diabetes; Phospho1 both directly and indirectly interacted with genes associated with glucose transport and insulin receptor signalling. Canonical thermogenesis via brown adipose tissue did not underlie the metabolic protection observed in adult Phospho1 −/− mice. However, the decreased serum choline levels in Phospho1 −/− mice were normalised by feeding a 2% choline rich diet resulting in a normalisation in insulin sensitivity and fat mass. Conclusion We show that mice lacking the bone mineralisation enzyme PHOSPHO1 exhibit improved basal glucose homeostasis and resist high-fat-diet-induced weight gain and diabetes. This study identifies PHOSPHO1 as a potential bone-derived therapeutic target for the treatment of obesity and diabetes.

The murine myostatin mutation MstnCmpt-dl1Abc (Compact; C) was introduced into an inbred mouse line with extreme growth (DUHi) by marker-assisted introgression. To study the allelic effects on muscle fibre hyperplasia and hypertrophy, myonuclear proliferation, protein accretion, capillary density, and muscle fibre metabolism, samples from M. rectus femoris (RF) and M. longissimus dorsi (LD) muscles of animals wild-type (+/+), heterozygous (C/+), and homozygous (C/C) for the MstnCmpt-dl1Abc allele were examined by histological and biochemical analyses. Homozygous C/C mice exhibited lower body (−12%) but higher muscle weights (+38%) than ++ mice. Total muscle fibre number was increased (+24%), whereas fibre size was not significantly affected. Protein and DNA concentrations and DNA:protein ratios as well as specific CK activity remained unchanged for higher mass muscle implying increases in the total contents of DNA and muscle specific protein. Fibre type distribution was markedly shifted to the white glycolytic muscle fibres (+16–17% units) at the expense of red oxidative fibres. Capillary density was substantially lower in C/C than in ++ mice as seen by lower number of capillaries per fibre (−35%) and larger fibre area per capillary (+77%). However, the MstnCmpt-dl1Abc allele was partially recessive in heterozyogous C/+ mice for both fibre type frequencies and capillary density. The results show that hypermuscularity caused by mutations in the myostatin gene results from muscle fibre hyperplasia rather than hypertrophy, and from balanced increases in myonuclear proliferation and protein accretion. However, capillary supply is adversely affected and muscle metabolism shifted towards glycolysis, which could have negative consequences for physical fitness. [ABSTRACT FROM AUTHOR]

The hypothesis that pigs placed on diets with reduced indispensable amino acid (AA) content attempts to offset the reduction in the nutrient density with increased feed intake was tested. In the experiment, feeds with a high or a low AA content were administrated to pigs fed ad-libitum or restrictively according to a 2 × 2 factorial design. Ninety-six barrows were housed in 8 pens (12 pigs/pen) equipped with automatic feeders. Within pen, and from 47 body weight (BW) onwards, 6 pigs were fed ad libitum. The others pigs were allowed to consume, as a maximum, the feed amounts indicated by the breeding company feeding plane to optimize the feed efficiency. In early (86-118 kg BW) and late (118-145 kg BW) finishing, the pigs of 4 pens received feeds with high indispensable AA contents (8.1 and 7.5 g lysine/kg in the two periods, respectively). The other pigs received feeds with reduced indispensable AA contents (lysine, methionine, threonine and tryptophan) by 9 and 18% in early and late finishing, respectively. Body lipid and protein (Pr) retentions were estimated from BW and back-fat depth measures recorded at the beginning and the end of each period. Nitrogen excretion was estimated as actual intake minus estimated N-retention (Pr/6.25). Pigs were slaughtered at 144 kg BW. Restricted feeding decreased feed intake (-7%), daily gain (-5%), carcass weight (-2.6%) and back-fat depth (-8.0%) but increased gain:feed ratio (+2%). The AA restriction increased feed intake (+5.9%), carcass weight (+4.9%) and intramuscular fat (+17.6%), and reduced carcass weight variation (-36%), with no effects on the feed efficiency and the estimated Pr (142 g/d). N excreted was reduced by feed (-9%) and dietary AA (-15%) restrictions. Irrespectively of the feeding level, the pigs responded to a reduction of the dietary essential AA content by increasing their feed intake.

Genetic background contributes substantially to individual variability in muscle mass. Muscle hypertrophy in response to resistance training can also vary extensively. However, it is less clear if muscle mass at baseline is predictive of the hypertrophic response.The aim of this study was to examine the effect of genetic background on variability in muscle mass at baseline and in the adaptive response of the mouse fast- and slow-twitch muscles to overload. Males of eight laboratory mouse strains: C57BL/6J (B6, n=17), BALB/cByJ (n=7), DBA/2J (D2, n=12), B6.A-(rs3676616-D10Utsw1)/Kjn (B6.A, n=9), C57BL/6J-Chr10A/J/NaJ (B6.A10, n=8), BEH+/+ (n=11), BEH (n=12) and DUHi (n=12), were studied. Compensatory growth of soleus and plantaris muscles was triggered by a 4-week overload induced by synergist unilateral ablation. Muscle weight in the control leg (baseline) varied from 5.2±07 mg soleus and 11.4±1.3 mg plantaris in D2 mice to 18.0±1.7 mg soleus in DUHi and 43.7±2.6 mg plantaris in BEH (p

BACKGROUND:Obesity and metabolic syndrome results from a complex interaction between genetic and environmental factors. In addition to brain-regulated processes, recent genome wide association studies have indicated that genes highly expressed in adipose tissue affect the distribution and function of fat and thus contribute to obesity. Using a stratified transcriptome gene enrichment approach we attempted to identify adipose tissue-specific obesity genes in the unique polygenic Fat (F) mouse strain generated by selective breeding over 60 generations for divergent adiposity from a comparator Lean (L) strain. RESULTS:To enrich for adipose tissue obesity genes a 'snap-shot' pooled-sample transcriptome comparison of key fat depots and non adipose tissues (muscle, liver, kidney) was performed. Known obesity quantitative trait loci (QTL) information for the model allowed us to further filter genes for increased likelihood of being causal or secondary for obesity. This successfully identified several genes previously linked to obesity (C1qr1, and Np3r) as positional QTL candidate genes elevated specifically in F line adipose tissue. A number of novel obesity candidate genes were also identified (Thbs1, Ppp1r3d, Tmepai, Trp53inp2, Ttc7b, Tuba1a, Fgf13, Fmr) that have inferred roles in fat cell function. Quantitative microarray analysis was then applied to the most phenotypically divergent adipose depot after exaggerating F and L strain differences with chronic high fat feeding which revealed a distinct gene expression profile of line, fat depot and diet-responsive inflammatory, angiogenic and metabolic pathways. Selected candidate genes Npr3 and Thbs1, as well as Gys2, a non-QTL gene that otherwise passed our enrichment criteria were characterised, revealing novel functional effects consistent with a contribution to obesity. CONCLUSIONS:A focussed candidate gene enrichment strategy in the unique F and L model has identified novel adipose tissue-enriched genes contributing to obesity.