GH receptor (GHR) gene-disrupted mice (GHR-/-) have provided countless discoveries as to the numerous actions of GH. Many of these discoveries highlight the importance of GH in adipose tissue. For example GHR-/- mice are insulin sensitive yet obese with preferential enlargement of the sc adipose depot. GHR-/- mice also have elevated levels of leptin, resistin, and adiponectin, compared with controls leading some to suggest that GH may negatively regulate certain adipokines. To help clarify the role that GH exerts specifically on adipose tissue in vivo, we selectively disrupted GHR in adipose tissue to produce Fat GHR Knockout (FaGHRKO) mice. Surprisingly, FaGHRKOs shared only a few characteristics with global GHR-/- mice. Like the GHR-/- mice, FaGHRKO mice are obese with increased total body fat and increased adipocyte size. However, FaGHRKO mice have increases in all adipose depots with no improvements in measures of glucose homeostasis. Furthermore, resistin and adiponectin levels in FaGHRKO mice are similar to controls (or slightly decreased) unlike the increased levels found in GHR-/- mice, suggesting that GH does not regulate these adipokines directly in adipose tissue in vivo. Other features of FaGHRKO mice include decreased levels of adipsin, a near-normal GH/IGF-1 axis, and minimal changes to a large assortment of circulating factors that were measured such as IGF-binding proteins. In conclusion, specific removal of GHR in adipose tissue is sufficient to increase adipose tissue and decrease circulating adipsin. However, removal of GHR in adipose tissue alone is not sufficient to increase levels of resistin or adiponectin and does not alter glucose metabolism.

The auditory system of the plainfin midshipman fish (<i>Porichthys notatus</i>) is an important sensory system used to detect and encode biologically relevant acoustic stimuli important for survival and reproduction including social acoustic signals used for intraspecific communication. Previous work showed that hair cell (HC) density in the midshipman saccule increased seasonally with reproductive state and was concurrent with enhanced auditory saccular sensitivity in both females and type I males. Although reproductive state-dependent changes in HC density have been well characterized in the adult midshipman saccule, less is known about how the saccule changes during ontogeny. Here, we examined the ontogenetic development of the saccule in four relative sizes of midshipman (larvae, small juveniles, large juveniles, and nonreproductive adults) to determine whether the density, total number, and orientation patterns of saccular HCs change during ontogeny. In addition, we also examined whether the total number of HCs in the saccule differ from that of the utricle and lagena in nonreproductive adults. We found that HC density varied across developmental stage. The ontogenetic reduction in HC density was concurrent with an ontogenetic increase in macula area. The orientation pattern of saccular HCs was similar to the standard pattern previously described in other teleost fishes, and this pattern of HC orientation was retained during ontogeny. Lastly, the estimated number of saccular HCs increased with developmental stage from the smallest larvae (2,336 HCs) to the largest nonreproductive adult (145,717 HCs), and in nonreproductive adults estimated HC numbers were highest in the saccule (mean ± SD = 28,479 ± 4,809 HCs), intermediate in the utricle (mean ± SD = 11,008 ± 1,619 HCs) and lowest in the lagena (mean ± SD = 4,560 ± 769 HCs).

As a negative regulator of muscle size, myostatin (Mstn) impacts the force-production capabilities of skeletal muscles. In the masticatory system, measures of temporalis-stimulated bite forces in constitutive myostatin KOs suggest an absolute, but not relative, increase in jaw-muscle force. Here, we assess the phenotypic and physiologic impact of postnatal myostatin inhibition on bite mechanics using an inducible conditional KO mouse in which myostatin is inhibited with doxycycline (DOX). Given the increased control over the timing of gene inactivation in this model, it may be more clinically-relevant for developing interventions for age-associated changes in the musculoskeletal system. DOX was administered for 12 weeks starting at age 4 months, during which time food intake was monitored. Sex, age and strain-matched controls were given the same food without DOX. Bite forces were recorded just prior to euthanasia after which muscle and skeletal data were collected. Food intake did not differ between control or DOX animals within each sex. DOX males were significantly larger and had significantly larger masseters than controls, but DOX and control females did not differ. Although there was a tendency towards higher absolute bite forces in DOX animals, this was not significant, and bite forces normalized to masseter mass did not differ. Mechanical advantage for incisor biting increased in the DOX group due to longer masseter moment arms, likely due to a more anteriorly-placed masseter insertion. Despite only a moderate increase in bite force in DOX males and none in DOX females, the increase in masseter mass in males indicates a potentially positive impact on jaw muscles. Our data suggest a sexual dimorphism in the role of mstn, and as such investigations into the sex-specific outcomes is warranted.

Myostatin, a negative regulator of muscle growth, is considered a potential therapeutic agent for individuals suffering from various muscle wasting and strength declining diseases because inhibiting Mstn signaling leads to muscular hypertrophy. In this study we investigate the interaction between myostatin and the growth hormone/insulin-like growth factor-1 (GH/IGF-1) axis in muscle function and strength. To this end, we measured hind limb grip strength and myostatin levels in two mouse models of GH gene manipulation; GH receptor knockout (GHR-/-) mice which have reduced GH/IGF-1 action, and bovine GH transgenic (bGH) mice which have excess GH/IGF-1 action. We found that specific muscle force was significantly reduced in bGH mice, and significantly increased in GHR-/- mice, compared to their respective littermate wild type controls. The expression of the mature form of myostatin was significantly increased in bGH mice, and unchanged in GHR-/- mice. In the bGH mice, the high levels of mature myostatin were accompanied by increase body weight and lean mass, consistent with other published results indicating that the IGF-1 signaling pathway is dominant over that of Mstn. Our results also suggest that in these mouse models there is an inverse relationship between muscle strength and levels of myostatin and GH, since constitutive overexpression of GH resulted in elevated levels of mature myostatin in muscle, accompanied by a reduction in strength. By contrast, in the GHR-/- mice with reduced levels of IGF-1, mature myostatin levels were unchanged and muscle strength was increased.

Purpose Mouse models are often used to validate novel interventions prior to human testing, although biological differences between mice and humans limit the translatability of outcomes. A common assumption in animal research is that maximal physical performance will be present at a young age, and that differences in task performance between young and old can be attributed to the aging process. However, this may not be true for all physical function tasks, and leaving out intermediate time points could drastically alter data interpretation. Basic procedures Here we document age-related changes in forelimb and hind-limb grip strength, balance and coordination, and body composition in mice (n = 43) collected at multiple time points between 4 and 24 months of age. Main findings Maximal forelimb grip strength was recorded at 4 months of age, but maximal hind-limb grip strength was recorded at 15 months of age. Balance performance was stable from 4-15 months of age, declining significantly at 18 months. Both lean and fat mass peaked at 18 months before declining steadily. Conclusions We conclude that the inclusion of intermediate time points is essential for accurate evaluation of physical function status in mice, particularly in the context of translating intervention outcomes into strategies to be tested in humans.