Motor neurone targeting of IGF-1 prevents specific force decline in ageing mouse muscle.
IGF-1 is a potent growth factor for both motor neurones and skeletal muscle. Muscle IGF-1 is known to provide target-derived trophic effects on motor neurones. Therefore, IGF-1 overexpression in muscle is effective in delaying or preventing deleterious effects of ageing in both tissues. Since age-related decline in muscle function stems partly from motor neurone loss, a tetanus toxin fragment-C (TTC) fusion protein was created to target IGF-1 to motor neurones. IGF-1-TTC retains IGF-1 activity as indicated by [(3)H]thymidine incorporation into L6 myoblasts. Spinal cord motor neurones effectively bound and internalized the IGF-1-TTC in vitro. Similarly, IGF-1-TTC injected into skeletal muscles was taken up and retrogradely transported to the spinal cord in vivo, a process prevented by denervation of injected muscles. Three monthly IGF-1-TTC injections into muscles of ageing mice did not increase muscle weight or muscle fibre size, but significantly increased single fibre specific force over aged controls injected with saline, IGF-1, or TTC. None of the injections changed muscle fibre type composition, but neuromuscular junction post-terminals were larger and more complex in muscle fibres injected with IGF-1-TTC, compared to the other groups, suggesting preservation of muscle fibre innervation. This work demonstrates that induced overexpression of IGF-1 in spinal cord motor neurones of ageing mice prevents muscle fibre specific force decline, a hallmark of ageing skeletal muscle.
Payne
Anthony M
AM
Department of Physiology and Pharmacology, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA.
Zheng
Zhenlin
Z
Messi
María Laura
ML
Milligan
Carol E
CE
González
Estela
E
Delbono
Osvaldo
O
D000375:Aging / Q000502:physiology; D000818:Animals; D002478:Cells, Cultured; D005786:Gene Expression Regulation; D007150:Immunohistochemistry; D007334:Insulin-Like Growth Factor I / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D051379:Mice; D008811:Mice, Inbred DBA; D009046:Motor Neurons / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D009119:Muscle Contraction / Q000187:drug effects; D009121:Muscle Denervation; D018485:Muscle Fibers, Skeletal / Q000145:classification / Q000187:drug effects / Q000502:physiology; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D009414:Nerve Growth Factors / Q000494:pharmacology; D009469:Neuromuscular Junction / Q000187:drug effects; D010446:Peptide Fragments / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D013116:Spinal Cord / Q000166:cytology; D013744:Tetanus Toxin / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D013936:Thymidine / Q000378:metabolism
D009414:Nerve Growth Factors; D010446:Peptide Fragments; D011993:Recombinant Fusion Proteins; D013744:Tetanus Toxin; C040635:tetanus toxin fragment C; D007334:Insulin-Like Growth Factor I; D013936:Thymidine