SBMA Seen to Affect Skeletal Muscles First, Not Motor Neurons

Although a disease of motor neurons, nerve cells of the spinal cord and brainstem, the earliest signs of spinal and bulbar muscular atrophy (SBMA) are in skeletal muscles, according to data from a mouse study.

These findings suggest that changes in muscle strength and contraction are early disease indicators, its researchers said, and  muscle-targeted therapies could be effective treatments for SBMA.

The findings, “Deterioration of muscle force and contractile characteristics are early pathological events in spinal and bulbar muscular atrophy mice,” were published in the journal Disease Models & Mechanisms.

SBMA, also known as Kennedy’s disease, is a rare, late-onset form of spinal muscular atrophy (SMA), characterized by widespread muscle weakness and wasting in the arms, legs, head, and neck (bulbar involvement).

This disorder is caused by mutations in the androgen receptor (AR) gene, located on the X chromosome and so most common to men. The mutations lead to an abnormal expansion of a CAG nucleotide (the building blocks of DNA) repeat in the AR gene sequence, and to the production of a much larger and dysfunctional protein.

Production of an enlarged protein is known to cause SBMA, but still unclear is why the disease affects specific types of motor neurons — nerve cells responsible for controlling voluntary muscles — and skeletal muscles, or those attached to bones and tendons that control voluntary movement.

“It is important to understand the course of the disease in order to target therapeutics to key pathological [disease] stages. This is especially relevant in disorders such as SBMA, where disease can be identified prior to symptom onset, through family history and genetic testing,” the researchers wrote.

Scientists at UCL Queen Square Institute of Neurology in London, working with colleagues at Duke University School of Medicine in North Carolina, did a complete characterization of the physiological basis underlying muscle dysfunction in a mouse model of SBMA.

They discovered the disease first manifested in skeletal muscles of the animals’ hind limbs, which started losing strength and the ability to contract when mice were 6 months old.

Loss of muscle strength continued to worsen until animals reached the age of 1 year, and then stabilized. In contrast, loss of muscle contraction continued, only becoming significant at later disease stages when mice were 12 to 18 months old.

Loss of muscle strength was accompanied by progressive muscle atrophy (shrinkage), as well as by a loss of body weight.

Histological examination of the animals’ muscle tissues revealed a series of abnormalities in the structure and organization of muscle fibers that started to become more apparent after animals were 1 year old.

To evaluate motor neuron degeneration, investigators assessed the number of motor neurons associated with the sciatic nerve — the large nerve that branches out of the lower back and runs down on each leg — in SBMA mice and healthy animals.

They found no differences in motor neuron numbers in 6-month-old SBMA mice compared to healthy animals, even though at this age diseased mice were already showing the first signs of muscular difficulties.

“Even by 12 months there was only a slight, but non-significant loss of motor neurons in [SBMA] mice, despite the very significant pathology observed in fast twitch muscles at this stage,” the researchers added.

These findings suggest that SBMA “first manifests in skeletal muscle in young mice, prior to any motor neuron degeneration, which only occurs in late stages of the disease.”

“Our results therefore show that muscle is a primary site of AR toxicity in SBMA, and suggest that targeting muscle deficits may be an effective therapeutic strategy for the treatment of the disease,” they concluded.