Dr. Jacqueline Montes and colleagues at Columbia University—part of the Pediatric Neuromuscular Clinical Research Network (PNCRN) funded by Cure SMA—have published a paper in the journal Annals of Clinical and Translational Neurology, titled “Diminished muscle oxygen uptake and fatigue in spinal muscular atrophy.”

This project, funded through the PNCRN, was an observational study evaluating muscle oxygen update and quantifying fatigue during exercise in ambulatory children and adults with SMA. Participants had to be at least 12 years old, and able to walk at least 25 meters without assistance and ride a stationary cycle ergometer.

Nineteen (19) ambulatory SMA and 16 healthy children and adults were evaluated. The participants with SMA were mostly male (73.7%) with a median age of 32.7 years (range 12.7–56.8). The control group participants were similar (81.2% male and median age 23.6 years; range 13.3–53.6). Of the 19 participants with SMA, 13 (68.4%) were treated with nusinersen, with a median treatment duration of 1.07 years (range 0.54–6.02). Overall, they observed that SMA is characterized by reduced muscle oxygen uptake, impaired response to exercise training, and debilitating fatigue—some of which may stem from intrinsic defects in the motor unit, such as mitochondrial dysfunction.

The results from this study add to the growing body of evidence suggesting that dysfunction in mitochondria—or structures within cells that generate energy—may contribute to the clinical symptoms experienced by individuals with SMA, including fatigue and reduced exercise capacity. This includes preclinical and clinical evidence of muscle, neuromuscular junction (NMJ), and motor neuron mitochondrial dysfunction. This is further supported by other clinical observations of persistent fatigue related to impaired neurotransmission, the process by which signaling molecules are released to communicate with other neurons and blunted responses to exercise conditioning.

Understanding these mechanisms underlying diminished muscle oxygen uptake and increased fatigue during exercise in SMA may reveal additional cellular targets for therapeutic intervention. Treating such tissues (i.e., muscle), especially in combination with SMN-enhancing therapeutics, may improve outcomes. More information about the study can be found at ClinicalTrials.gov (NCT02895789).

About the Pediatric Neuromuscular Clinical Research Network (PNCRN)

The Pediatric Neuromuscular Clinical Research Network (PNCRN) was established to create a team of SMA clinical trial experts that would integrate clinical research, education, and care to help achieve the best possible clinical trial outcomes for the SMA community. The  PNCRN has been involved in the seminal clinical trials that have led to the U.S. Food and Drug Administration (FDA) approvals of breakthrough SMA treatment options that have changed forever the natural course of the disease. Six sites comprise the PNCRN for SMA: Boston Children’s Hospital, Boston, MA; Children’s Hospital of Philadelphia, Philadelphia, PA; Columbia University Irving Medical Center, New York, NY; Nemours Children’s Health System, Orlando FL; Stanford University, Palo Alto, CA; and the data coordinating center at the University of Rochester, Rochester, NY.