Early morphological remodeling of neuromuscular junction in a murine model of diabetes

Abstract

Although skeletal muscle weakness is documented in diabetes, the time course for its development is not established. The present study examined the dorsiflexor muscle from animals that had been diabetic for 2 wk. Adult male c57BL mice were injected once with streptozotocin (STZ) to induce diabetes (60 mg/kg ip). Two weeks later, resting membrane potential and miniature end-plate potentials were recorded, and electron microscopy was utilized for ultrastructural evaluations. After STZ-induced diabetes, both resting membrane potential and miniature end-plate potentials were reduced. Nerve terminals showed less synaptic vesicles and had degenerated mitochondria. Furthermore, in the intramuscular nerves, disorganization of microtubules and neurofilaments was evidenced. Myelin-like figures were present in intramuscular nerves, neuromuscular junctions, and muscle fibers. At the muscle level, mitochondria were swollen, with disorganization of their cristae, disruption of T tubules, and myofibers with more deposition of glycogen granules. The present results revealed early STZ-induced nerve and muscle alterations. Observed ultrastructural modifications resemble those of motoneuron disorders and aging processes. These changes are possibly related to alterations in Ca(2+) mobilization across muscle membrane. Other mechanisms such as free radical-mediated actions may also be implicated in STZ-induced effects on skeletal muscle.

Motor unit number estimate as a predictor of motor dysfunction in an animal model of type 1 diabetes

“…At 2 wk after STZ was administered, they observed reductions in the amplitude of both resting membrane potential and miniature end plate potentials. These authors also describe fewer synaptic vesicles and mitochondrial abnormalities as well as ultrastructural changes in the diabetic NMJ similar to those of motor neuron disorder and aging (13,14). These later observations could help explain the reduction in QC seen in our diabetic mice.…”

“…Fahim et al (14) examined the dorsiflexor muscle from STZ-diabetic mice. At 2 wk after STZ was administered, they observed reductions in the amplitude of both resting membrane potential and miniature end plate potentials.…”

Skeletal muscle dysfunction in the db/db mouse model of type 2 diabetes

“…11 Evidence for possible transmission failure as a result of reduced synaptic safety factor in diabetes comes from studies showing reduced acetylcholine release in streptozotocin (STZ)-based murine models of diabetes. 22,23 At the same time, however, increased acetylcholine sensitivity has also been shown in STZ-induced diabetes. 24,25 Together with the observation that muscles from both STZ mice and db/db mice show decreased acetylcholinesterase gene expression, 25 this could indicate that the potential impairment of neuromuscular transmission arising from reduced acetylcholine release is compensated, at least to some extent, by mechanisms that increase the postsynaptic effect of the acetylcholine that is actually released.…”

Future treatments for diabetic neuropathy: Clues from experimental neuropathy

“…This is a relatively short period compared with the long duration of disease in diabetic patients and it may contribute to the major shortfall of the rodent models of diabetes-which is that they do not develop overt pathologic signs of peripheral neuropathy. There are subtle structural changes in the nerves of diabetic rats after a few months of hyperglycemia, such as reduced axonal caliber [4], myelin splitting in the spinal roots [5], and ultrastructural pathology in the peripheral and central nerve terminals that could represent early signs of distal axonopathy [6,7]. Suggestions originating from studies that examined neurons grown under hyperglycemic conditions in vitro showing that there was evidence of apoptosis in the ganglia of diabetic rats [8,9] have prompted reconsideration of the effects of diabetes on the nerve structure in diabetic rats.…”