Exciting possibility: Drugs used to treat spinal muscular atrophy could be repurposed to treat age-related muscle dysfunction
The consequences of sarcopenia are often severe in older adults, contributing to a number of adverse health outcomes, including loss of function, disability, frailty and increase of death. Most sarcopenia research has been muscle-centric, focused on methods to improve muscle strength by increasing muscle mass. Progress has been modest, leading some researchers—including W. David Arnold, MD—to explore nervous system integrity as a factor in age-related loss of muscle function.
Dr. Arnold, a nerve and muscle disease expert at The Ohio State University Wexner Medical Center, is leading a National Institutes of Health-funded study to explore whether the survival motor neuron (SMN) protein plays a role in the pathogenesis of muscle dysfunction as we age. His interest in the SMN protein dates back to 2013, when he began participating in the preclinical development of spinal muscular atrophy (SMA) gene therapies, including Zolgensma.
What’s the connection between SMA and age-related sarcopenia?
Dr. Arnold: SMA is a group of hereditary diseases that progressively destroy muscle neurons in the spinal cord that control muscle activity. Sarcopenia is loss of muscle mass, which is an important contributor to impaired physical function in older adults. My lab published a paper two years ago demonstrating that the spinal motor neurons that die in SMA appear to play an important role in causing sarcopenia.
This discovery builds upon work in SMA that took place 20 years ago at The Ohio State University under the guidance of Arthur Burghes, PhD, when a mouse model of SMA was generated with higher-than-normal levels of the SMN protein. My lab did early experiments on these mice, and it seems that mice with higher levels of the SMN protein have better muscle function and resilience.
How does your current SMN research relate to this finding?
Dr. Arnold: I’m leading an NIH-funded basic research study to explore whether increased levels of the SMN protein could help improve maintenance or repair of muscle dysfunction that occurs as part of the aging process. Our work so far provides evidence to suggest that SMN gene expression decreases in aging. When we put an extra SMN gene in older mice, the transgenic mice seem not to become sarcopenic. They show improvement of muscle maintenance and improved muscle repair following injury.
This study will also explore the role that the SMN protein plays in maintaining connectivity between the nervous system and muscle. This connection is critical to maintaining muscle strength.
What are the potential therapeutic agents that could emerge from this work?
Dr. Arnold: Developing therapeutics for age-related muscle dysfunction that target the nervous system is a novel strategy—we aren’t aware of anyone else doing this work right now. Our work is timely when you consider that, in the last five years, three new therapies have become clinically available to treat people with SMA. These include Spinraza, Zolgensma and Evrysdi. We could potentially repurpose these therapies for people whose severe sarcopenia is related to aging or other factors, such as muscle weakness after hospitalization.
About 10% of individuals over the age of 65 are affected by sarcopenia, with the frequency climbing to over 50% by age 80. Loss of muscle function is a significant concern for older adults, affecting their ability to be independent and increasing their risk for falls, frailty and osteoporosis, among other issues. Thanks to scientific breakthroughs related to SMA drug development, we may be closer to an effective therapy for sarcopenia than we think.