Restoring cellular energetics promotes axon regeneration and functional recovery after spinal cord injury

Cell Metab, 2020 · DOI: 10.1016/j.cmet.2020.02.002 · Published: March 3, 2020

Spinal Cord Injury Regenerative Medicine Neurology

Simple Explanation

Mature central nervous system (CNS) neurons typically fail to regenerate after injury, leading to permanent neurological impairments. Prior studies have elucidated genetic programs, signaling mechanisms, and extracellular inhibitory factors affecting axonal regeneration. For successful regeneration, injured axons must reseal injured terminals, reconstruct cytoskeleton, synthesize and transport building materials, assemble axon components, and form growth cones. Combined with the increased energy demand of regeneration, injured axons face a net energy deficit. We hypothesize that recovery of local energy supply may be critical to support regeneration of injured long-projection axons, such as the corticospinal tract (CST).

Study Duration

8 weeks

Participants

Adult Snph−/− mice and wild-type controls

Evidence Level

Not specified

Key Findings

1
Enhancing axonal mitochondrial transport via genetic Snph deletion in mice recovered injury-induced mitochondrial damage.
2
Enhancing axonal mitochondrial transport via genetic Snph deletion in mice promoted axon regeneration and synaptic connection following SCIs.
3
Enhancing axonal mitochondrial transport via genetic Snph deletion in mice restored motor functions.

Research Summary

Axonal regeneration in the central nervous system (CNS) is a highly energy demanding process. Extrinsic insults and intrinsic restrictions lead to an energy crisis in injured axons, raising the question of whether recovering energy deficits facilitates regeneration. Administration of the bioenergetic compound creatine boosts CST regenerative capacity in Snph−/− mice. Our study provides mechanistic insights into intrinsic regeneration failure in CNS and suggests that enhancing mitochondrial transport and cellular energetics is a promising strategy to promote regeneration and functional restoration after CNS injuries. Our study establishes that injury-induced “energy crisis” contributes to CNS regeneration failure after SCI. Recovering local energy by either enhancing mitochondrial transport or by increasing energy metabolism promotes axonal sprouting and regeneration after SCI.

Practical Implications

Therapeutic Target

Enhancing mitochondrial transport and cellular energetics represents a promising therapeutic direction to stimulate axonal regeneration and functional recovery after spinal cord injury.

Clinical Translation

The study suggests a new cellular target for stimulating regeneration and functional recovery after CNS injuries, particularly in the spinal cord.

Combination Therapies

Reversing energy crisis would be expected to further boost axon regeneration when combined with other interventions known to enhance regrowth following CNS injuries.

Study Limitations

1
C5 DH is an ideal SCI model to study CST axon regeneration and assess functional recovery of forelimb dexterity, however, this injury model likely maintains CST innervation of motoneurons at C2-C4 spinal levels and spares other descending pathways.
2
Given the technical challenge of monitoring in vivo ATP and ROS levels in injured spinal cord using ATP and redox probes, we alternatively applied microfluidic devices to study injury-triggered ATP reduction and mitochondrial ROS response in live neurons.
3
Systemic administration of creatine has rather limited effect on facilitating axonal regeneration after SCI when compared to enhanced mitochondrial transport in Snph−/− mice.

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