45 research outputs found
Exercise training attenuates the hypermuscular phenotype and restores skeletal muscle function in the myostatin null mouse
No full textMyostatin regulates both muscle mass and muscle metabolism. The myostatin null (MSTN-/-) mouse has a hypermuscular phenotype owing to both hypertrophy and hyperplasia of the myofibres. The enlarged muscles display a reliance on glycolysis for energy production; however, enlarged muscles that develop in the absence of myostatin have compromised force-generating capacity. Recent evidence has suggested that endurance exercise training increases the oxidative properties of muscle. Here, we aimed to identify key changes in the muscle phenotype of MSTN-/- mice that can be induced by training. To this end, we subjected MSTN-/- mice to two different forms of training, namely voluntary wheel running and swimming, and compared the response at the morphological, myocellular and molecular levels. We found that both regimes normalized changes of myostatin deficiency and restored muscle function. We showed that both exercise training regimes increased muscle capillary density and the expression of Ucp3, Cpt1a, Pdk4 and Err?, key markers for oxidative metabolism. Cross-sectional area of hypertrophic myofibres from MSTN-/- mice decreased towards wild-type values in response to exercise and, in this context, Bnip3, a key autophagy-related gene, was upregulated. This reduction in myofibre size caused an increase of the nuclear-to-cytoplasmic ratio towards wild-type values. Importantly, both training regimes increased muscle force in MSTN-/- mice. We conclude that impaired skeletal muscle function in myostatin-deficient mice can be improved through endurance exercise-mediated remodelling of muscle fibre size and metabolic profil
BMP signaling controls muscle mass.
No full textCell size is determined by the balance between protein synthesis and degradation. This equilibrium is affected by hormones, nutrients, energy levels, mechanical stress and cytokines. Mutations that inactivate myostatin lead to excessive muscle growth in animals and humans, but the signals and pathways responsible for this hypertrophy remain largely unknown. Here we show that bone morphogenetic protein (BMP) signaling, acting through Smad1, Smad5 and Smad8 (Smad1/5/8), is the fundamental hypertrophic signal in mice. Inhibition of BMP signaling causes muscle atrophy, abolishes the hypertrophic phenotype of myostatin-deficient mice and strongly exacerbates the effects of denervation and fasting. BMP-Smad1/5/8 signaling negatively regulates a gene (Fbxo30) that encodes a ubiquitin ligase required for muscle loss, which we named muscle ubiquitin ligase of the SCF complex in atrophy-1 (MUSA1). Collectively, these data identify a critical role for the BMP pathway in adult muscle maintenance, growth and atrophy
Hindlimb muscle contractile properties in acetylcholinesterase knockout mice
No full textNational audienc
Hindlimb muscle contractile properties in acetylcholinesterase knockout mice
No full textNational audienc
Genetic ablation of acetylcholinesterase alters muscle function in mice.
No full textAlthough acetylcholinesterase (AChE) knockout mice survive, they have abnormal neuromuscular function. We analysed further the effects of the mutation on hind limb muscle contractile properties. Tibialis anterior muscle from AChE KO mice is unable to maintain tension during a short period of repetitive nerve stimulation (tetanic fade) and has an increased twitch tension in response to a single nerve electric stimulation. In response to direct muscle stimulation, we found that maximal velocity of shortening of soleus muscle is increased and maximum tetanic force is decreased in AchE KO mice versus control animals. As the contractile properties of the soleus muscle were altered by AChE ablation, our results suggest cellular and molecular changes in AChE ablated muscle containing both fast and slow muscle fibres
Outcome of acetylcholinesterase deficiency for neuromuscular functioning
No full textAcetylcholinesterase (AChE) plays an essential role in neuromuscular transmission, therefore it is surprising that AChE knockout (KO) mice could live to the adulthood. Neuromuscular functioning in KO and normal (wild type, WT) mice were studied, at different age (1.5-, 4- and 9-month-old). Hindlimb muscle force productions in response to nerve or muscle electric stimulation were recorded in situ and in vitro. Our results show that contrary to WT mice, 1.5-, 4- and 9-month-old KO mice exhibited a decreased in tetanic force during short periods (500 ms) of repetitive nerve stimulations (tetanic fade). Nevertheless submaximal muscle forces in response to single or repetitive nerve stimulation were increased (potentiation) in 1.5-, 4- and 9-month-old KO mice as compared to WT mice (p 0.05). In conclusion AChE deficit leads to marked neuromuscular alterations in hind limb muscle functioning and a prominent symptom is the lack of resistance to fatigue
Impact of impaired neuromuscular transmission on skeletal muscle physiology in three murine models with neuromuscular junction defects
No full textIncreased ventilation and CO2 chemosensitivity in acetylcholinesterase knockout mice.
No full textTo investigate the effects of a permanent excess of acetylcholine (AChE) on respiration, breathing and chemosensitivity were analyzed from birth to adulthood in mice lacking the AChE gene (AChE-/-), in heterozygotes, and in control wild-type (AChE+/+) littermates. Breathing at rest and ventilatory responses to brief exposures to hypoxia (10% O2) and hypercapnia (3-5% CO2) were measured by whole-body plethysmography. At rest AChE-/- mice show larger tidal volumes (VT, + 96% in adults), overall ventilation (VE, + 70%), and mean inspiratory flow (+270%) than wild-type mice, with no change in breathing frequency (fR). AChE-/- mice have a slightly blunted response to hypoxia, but increased VE and fR responses to hypercapnia. Heterozygous animals present no consistent alterations of breathing at rest and chemosensitivity is normal. Adult AChE-/- mice have an increased VE/VO2 and a marginally higher normalized VO2. The results suggest that the hyperventilation and altered chemosensitivity in AChE-/- mice largely reflect alterations of central respiratory control
