Damage to muscle spindles may cause Pompe motor problems
Muscle spindle function was 'severely compromised' in preclinical study of mice
Motor problems in people with Pompe disease may be explained by damage to muscle spindles, which are sensory receptors that detect muscle movement and help regulate muscle tone and maintain posture, a mouse study suggested.
Muscle spindle structure and function were “severely compromised” in Pompe mice, resulting in a lack of sensitivity to muscle movement and problems coordinating limb movements.
The mouse study, “Degeneration of muscle spindles in a murine model of Pompe disease,” was published in the journal Scientific Reports.
Pompe disease is a genetic disorder caused by a deficiency in the acid alpha-glucosidase (GAA) enzyme, responsible for breaking down glycogen, a complex sugar molecule that serves as an energy source.
GAA deficiency leads to toxic glycogen accumulation in various organs and tissues, particularly the muscles. Such a buildup can cause progressive muscle weakness and atrophy (shrinkage), affecting motor function and potentially breathing.
However, “the cause of the impaired motor control is unknown,” wrote researchers at the Ludwig-Maximilians-University, in Germany.
Muscle spindles are specialized sensory receptors that provide feedback to the nervous system about muscle movement. Stretching muscles activate sensory nerves within the spindle, sending signals to the spinal cord. Accordingly, muscle spindles are essential for maintaining muscle tone and controlling movements.
The researchers hypothesized that impaired muscle spindle function might contribute to motor problems in people with Pompe.
Testing intervals at 4 and 8 months
To test it, the team examined motor and muscle spindle function in Pompe mice lacking the gene that provides instructions to make the GAA enzyme at 4 and 8 months of age.
Detailed motor function analysis identified numerous deficiencies in Pompe mice not found in healthy control mice. While some of these differences were due to reduced muscle strength and lower body weight, several altered parameters related to limb coordination were consistent with impaired motor control.
At 4 months old, Pompe mice had abnormal step positions, a greater distance between the two hind paws, and more footprints outside of a recognized pattern. At four and eight months, the paw print position — the distance between the back paw and the previously placed front paw — was increased on both sides of the body.
Muscle spindle function was assessed using electrophysiological analysis, which detected the electrical signals of sensory nerves connected to a lower limb muscle. Tissue from all controls, 4-month-old Pompe mice, and about 70% of 8-month-old mice responded to a muscle stretch with an increased signal frequency.
However, the response frequencies to different muscle stretches were significantly lower in Pompe mice of both ages. Frequency responses over time during all stretches also were lower in Pompe mice, demonstrating “impaired sensitivity of the dynamic [moving] and static [not moving] component of the stretch response,” the team wrote.
Overall, sensitivity to the muscle stretch was markedly reduced in Pompe mice at both ages and entirely insensitive to stretch movement in about 30% of the older mice.
Muscle tissue examination detected progressive structural degeneration of muscle spindles and reduced numbers in Pompe mice. Sensory nerves also were withdrawn from the muscle spindle and showed damage.
Autophagy disrupted
Because the GAA enzyme is located in lysosomes, the cell’s recycling centers, its deficiency, and the subsequent buildup of glycogen, disrupt the entire recycling process called autophagy. Experiments confirmed an increase in the number and size of lysosomes in muscle spindles from the older Pompe mice.
At the same time, there was a buildup of autophagosomes — tiny sacs that deliver cellular waste to lysosomes to be recycled — suggesting that “abnormal autophagy might contribute to the severe degenerative processes of the muscle spindles,” the team noted.
“These results demonstrate a structural and functional degeneration of muscle spindles and an altered motor coordination in [Pompe] mice,” the researchers wrote. “Similar changes could contribute to the impaired motor coordination in patients living with Pompe disease.”
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