This proposal is to develop techniques for minimizing and/or reversing muscle atrophy and degeneration after complete denervation, a common problem associated with various neuromuscular disorders and trauma. Preliminary experiments show that embryonic ventral spinal cord cells, including presumptive motoneurons, placed in the distal stump of cut peripheral nerves, send axons into the denervated muscle to innervate it effectively. However, improvements are sought in the extent and nature of the reinnervation. Such interventions provide the possibility of preserving muscle function for longer periods pending reinnervation by surviving and regenerating native axons, or, in cases in which this cannot occur, stimulating the reinnervated nerves artificially to produce useful behaviors from the resulting muscle responses.
The specific aims are: 1) compare motoneuron survival and axon growth in cases in which cells are transplanted immediately after nerve section versus those in which the nerve has had time to degenerate (10 weeks); 2) assess effects of trophic factor delivery to the transplant on motoneuron survival and axon growth; 3) assess effects of long-term trophic factor treatment of the muscle on its size and strength; 4) assess effects of long-term treatment of the muscle by pharmacological agents on its size and strength; 5) assess effects of combined interventions; 6) assess effects of electrically stimulated neural activity on muscle strength and fatigue-resistance. Anatomical measures of effective transplants will include the number and size of surviving motoneurons in the transplant, number and diameter of myelinated axons in the innervated peripheral nerves, presence of neuromuscular junctions in the innervated muscles, muscle weight and muscle fiber area and type. Functional measures will include medial and lateral gastrocnemius muscle and motor unit strength, speed and fatigability, number of reinnervated motor units, and the axon conduction velocity of the innervating fibers. The functional measures will be assessed for relationships with the anatomical findings.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Special Emphasis Panel (ZRG1-IFCN-5 (01))
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Mitler, Merrill
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University of Miami School of Medicine
Schools of Medicine
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Liu, Yang; Grumbles, Robert M; Thomas, Christine K (2014) Electrical stimulation of transplanted motoneurons improves motor unit formation. J Neurophysiol 112:660-70
Grumbles, Robert M; Liu, Yang; Thomas, Christie M et al. (2013) Acute stimulation of transplanted neurons improves motoneuron survival, axon growth, and muscle reinnervation. J Neurotrauma 30:1062-9
Liu, Yang; Grumbles, Robert M; Thomas, Christine K (2013) Electrical stimulation of embryonic neurons for 1 hour improves axon regeneration and the number of reinnervated muscles that function. J Neuropathol Exp Neurol 72:697-707
Grumbles, Robert M; Almeida, Vania W; Casella, Gizelda T B et al. (2012) Motoneuron replacement for reinnervation of skeletal muscle in adult rats. J Neuropathol Exp Neurol 71:921-30
Casella, Gizelda T B; Almeida, Vania W; Grumbles, Robert M et al. (2010) Neurotrophic factors improve muscle reinnervation from embryonic neurons. Muscle Nerve 42:788-97
Grumbles, Robert M; Sesodia, Sanjay; Wood, Patrick M et al. (2009) Neurotrophic factors improve motoneuron survival and function of muscle reinnervated by embryonic neurons. J Neuropathol Exp Neurol 68:736-46
Grumbles, Robert M; Almeida, Vania W; Thomas, Christine K (2008) Embryonic neurons transplanted into the tibial nerve reinnervate muscle and reduce atrophy but NCAM expression persists. Neurol Res 30:183-9
Grumbles, Robert M; Casella, Gizelda T B; Rudinsky, Michelle J et al. (2007) Long-term delivery of FGF-6 changes the fiber type and fatigability of muscle reinnervated from embryonic neurons transplanted into adult rat peripheral nerve. J Neurosci Res 85:1933-42
Grumbles, R M; Casella, G T B; Rudinsky, M J et al. (2005) The immunophilin ligand FK506, but not the P38 kinase inhibitor SB203580, improves function of adult rat muscle reinnervated from transplants of embryonic neurons. Neuroscience 130:619-30
Baez, Juan Carlos; Gajavelli, Shyam; Thomas, Christine K et al. (2004) Embryonic cerebral cortex cells retain CNS phenotypes after transplantation into peripheral nerve. Exp Neurol 189:422-5

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