Date of Award
Master of Science
Dr. Erich Ottem
Brain-derived neurotrophic factor (BDNF) is a neurotrophin required for the differentiation, growth, and survival of neurons. BDNF is synthesized in several tissue types including skeletal muscle. Neuromuscular diseases (NMDs) are characterized by the degeneration of motorneurons and/or associated skeletal muscles, and reduced BDNF is implicated in NMDs. Using Cre-Lox gene recombination technology our lab generated transgenic mice in which the BDNF gene was knocked out of skeletal muscle. We hypothesized that skeletal muscle-BDNF is required for normal retrograde transport of proteins and mitochondria along gastrocnemius-associated motorneuron axons. We first measured accumulation of the retrogradely transported phosphorylated neurofilament-H (NF-H-P) protein at distal motorneuron axons in young (30 day old; 30d) and young-adult (120d) transgenic mice. We show significant accumulation of NF-H-P at the distal axon in 120d muscle-BDNF deficient mice, but not in 30d animals. Sciatic nerve ligation experiments show significantly less accumulation of NF-H-P and the motor associated protein, dynactin 1, immediately distal to the ligation site in muscle-BDNF deficient mice at 120d, but not at 30d. These results indicate that loss of muscle-synthesized BDNF leads to disruptions in retrograde transport in 120d animals. To investigate potential accumulation of mitochondria at the presynapse, we injected the mitochondrial dye MitoTracker into the gastrocnemius muscle of 120d transgenic animals and measured colocalization of this dye with presynaptic and postsynaptic immunofluorescent markers. Our results reveal a significant decrease in mitochondria at the presynaptic terminal in 120d muscle-BDNF deficient mice.
Dangremond, Rebecca L., "THE ROLE OF SKELETAL MUSCLE-SYNTHESIZED BRAIN-DERIVED NEUROTROPHIC FACTOR IN RETROGRADE TRANSPORT ALONG MOTORNEURON AXONS" (2016). All NMU Master's Theses. 77.