Muscle specific kinase protects dystrophic mdx mouse muscles from eccentric contraction-induced loss of force-producing capacity.
S TrajanovskaJ BanJ HuangP GregorevicMarco MorschDavid G AllenWilliam D PhillipsPublished in: The Journal of physiology (2019)
Muscle specific kinase (MuSK) has a well-defined role in stabilizing the developing mammalian neuromuscular junction, but MuSK might also be protective in some neuromuscular diseases. In the dystrophin-deficient mdx mouse model of Duchenne muscular dystrophy, limb muscles are especially fragile. We injected the tibialis anterior muscle of 8-week-old mdx and wild-type (C57BL10) mice with adeno-associated viral vectors encoding either MuSK or rapsyn (a cytoplasmic MuSK effector protein) fused to green fluorescent protein (MuSK-GFP and rapsyn-GFP, respectively). Contralateral muscles injected with empty vector served as controls. One month later mice were anaesthetized with isoflurane and isometric force-producing capacity was recorded from the distal tendon. MuSK-GFP caused an unexpected decay in nerve-evoked tetanic force, both in wild-type and mdx muscles, without affecting contraction elicited by direct electrical stimulation of the muscle. Muscle fragility was probed by challenging muscles with a strain injury protocol consisting of a series of four strain-producing eccentric contractions in vivo. When applied to muscles of mdx mice, eccentric contraction produced an acute 27% reduction in directly evoked muscle force output, affirming the susceptibility of mdx muscles to strain injury. mdx muscles overexpressing MuSK-GFP or rapsyn-GFP exhibited significantly milder force deficits after the eccentric contraction challenge (15% and 14%, respectively). The protective effect of MuSK-GFP in muscles of mdx mice was associated with increased immunolabelling for utrophin and β-dystroglycan in the sarcolemma. Elevating the expression of MuSK or rapsyn revealed several distinct synaptic and extrasynaptic effects, suggesting novel roles for MuSK signalling in muscle physiology and pathophysiology.
Keyphrases
- duchenne muscular dystrophy
- wild type
- skeletal muscle
- resistance training
- muscular dystrophy
- single molecule
- high fat diet induced
- mouse model
- randomized controlled trial
- smooth muscle
- type diabetes
- spinal cord injury
- metabolic syndrome
- immune response
- traumatic brain injury
- living cells
- quantum dots
- insulin resistance
- minimally invasive
- molecular dynamics simulations
- tyrosine kinase
- regulatory t cells
- binding protein
- endothelial cells
- adipose tissue
- amino acid
- protein protein
- small molecule
- high glucose