Effect of Postnatal Myostatin Inhibition on Bite Mechanics in Mice

Abstract

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.

Relative Contributions of Myostatin and the GH/IGF-1 Axis in Body Composition and Muscle Strength

“…While both GH and IGF-1 are associated with increased muscle performance ( Gläser et al, 2010 ; Taekema et al, 2011 ), the effect of Mstn on muscle strength remains unclear. We have reported ( Williams et al, 2015 ) that MSTN inhibition may enhance overall strength due to hypertrophy, but that specific muscular force is not significantly different when normalized to muscle wet weights. Other studies have found that muscle fiber function is significantly reduced in MSTN -/- mice relative to muscle weights ( Amthor et al, 2007 ; Gentry et al, 2011 ).…”

“…Muscle wasting is linked to excess Mstn in circulation ( Gonzalez-Cadavid et al, 1998 ; Marcell et al, 2001 ; Costelli et al, 2008 ). Mice overexpressing Mstn have less skeletal muscle than littermate controls ( Thomas et al, 2000 ; Lee, 2004 ; Huang et al, 2011 ), while MSTN gene mutations and reduced protein levels increase muscle mass ( Kambadur et al, 1997 ; Lin et al, 2002 ; Schuelke et al, 2004 ; Mosher et al, 2007 ; Williams et al, 2015 ).…”

Ontogenetic and in silico models of spatial‐packing in the hypermuscular mouse skull

“…However, in our -/-mouse model the spatial-packing problem of enlarged musculature is conflated with reduced brain size, possibly due to suppressed myostatin expression within the brain (see Discussion), and with the structural effects of increased muscle and bite force (e.g. Byron et al, 2006;Williams et al, 2015). We therefore inferred the extricated and combined effects of brain and muscle growth on skull architecture in-silico and in doing so we also evaluate the ability of simple deformation to describe spatial-packing related phenomena.…”

‘Double-muscling’ and pelvic tilt phenomena in rabbits with the cystine-knot motif deficiency of myostatin on exon 3

“…The mice were also used to indicate that a consistent amount of force needs to be applied over a much greater area of the craniofacial skeleton in the myostatin knockout, and this should, in turn, lead to altered biomechanical stress and bony morphology [3,16]. An MSTN −/− mouse has significantly larger temporalis, masseter, and medial and lateral pterygoid muscles than WT controls [17]. These characteristics, coupled with morphologic findings of the skull in MSTN −/− mice (e.g., shorter crania, longer, and rounder mandibles), provide further evidence of an altered craniofacial loading environment due to MSTN deficiency [3,16–20].…”