Energy Problems in Muscle Cells of Type 3 Patients Evident in Exercise Study

Poorer oxygen update in muscle cells and greater fatigue was evident among ambulatory spinal muscular atrophy (SMA) patients relative to healthy people in an exercise-based study, suggesting that problems in cell energy production play a role in this disease.

A better understanding of the mechanisms involved in oxygen uptake by muscle cells during exercise may lead to new treatment targets, its scientists said. 

The study, “Diminished muscle oxygen uptake and fatigue in spinal muscular atrophy,” was published in the Annals of Clinical and Translational Neurology.

SMA is characterized by progressing muscle weakness caused by the loss of motor neurons, which are specialized nerve cells in the brain and spinal cord that control voluntary movement. 

Muscle tissue isolated from SMA patients has shown depleted and impaired mitochondria, known as the cell’s powerhouses. Mitochondria use available oxygen within cells to convert food into chemical energy. 

Studies report that people with milder SMA types show diminished responses to physical conditioning programs with only modest improvements in exercise capabilities. Shorter and more intensive conditioning programs lead to similar improvements and severe fatigue.

Symptoms of SMA type 3 usually become evident after a child has learned to walk or stand; abilities these patients often lose as they age. Studying exercise in this patient population, which allows for more detailed assessments of aerobic capacity and muscle function, help to inform understanding of the disease’s more severe forms.

Researchers at Columbia University Irving Medical Center, working with the National Institutes of Health and the Muscular Dystrophy Association, opened a study (NCT02895789) in type 3 patient of muscle oxygen uptake and fatigue during exercise and its relationship to body composition. 

A total of 19 ambulatory (able to walk) SMA were included, most males (73.7%) with a median age of 32.7 (range, 12 to 57). The median age at symptom onset was 7 (range, 1.5 to 16 years old), and their median disease duration was almost 23 years (from five to 55 years). 

Most patients, 13 or 68.4%, were being treated with Spinraza (nusinersen), a disease-modifying treatment for all types of SMA. A control group of 16 healthy children and adults of similar ages were assessed for comparison. 

Participants underwent cardiopulmonary exercise testing (CPET) using a stationary bicycle, with pedal shoes and straps to ensure a stable foot placement. Oxygen uptake and related variables were measured, and peak oxygen uptake (VO2-peak) was expressed relative to total body mass and lean body mass, which is the difference between total body weight and body fat weight. The team also assessed peak workload (W-peak). 

A 10‐minute submaximal (less than maximum) exercise test was performed on the cycle after a 30‐minute rest period, in which the workload was set at 40% of the peak workload achieved on the cardiopulmonary exercise testing. 

Near-infrared spectroscopy, via a patch attached to the thigh, measured oxygen saturation in muscles. Relative changes in deoxygenated hemoglobin, the protein in red blood cells that carries oxygen through the body, were calculated. 

Fatigue during the submaximal exercise test was calculated as the percent change in workload from the first minute to the 10th minute (Fatigue-SME). Fatigue was also measured during a six-minute walking test (Fatigue-6MWT), calculated by subtracting the distance walked in six minutes from the distance walked in the first minute.

Analysis found that, compared to controls, SMA patients had a significantly lower oxygen uptake-peak relative to total body mass as well as lean body mass. This finding likely reflected “a combination of deconditioning due to insufficient physical activity and abnormal muscle oxygen uptake,” the researchers wrote. 

SMA patients also had a lower workload peak and a lesser change in deoxygenated hemoglobin from rest to maximal effort during cardiopulmonary exercise testing. Findings here suggested “SMA patients may rely to a greater extent on anaerobic metabolic pathways (without oxygen) early in exercise compared with healthy people,” the team added. 

During submaximal exercise, the change in deoxygenated hemoglobin and the distance walked in six minutes was also significantly poorer in SMA than in healthy controls. 

Both Fatigue-6MWT and Fatigue-SME were significantly higher in SMA, and minimal in controls. Individuals with SMA also had a lower fat-free mass (57.5%), a measure similar to total lean body mass that does not include any fuel fat, than did controls (77.7%). 

A statistical analysis found in  a higher oxygen uptake-peak significantly correlated with a higher fat-free mass along with workload peak for both patients and controls. In controls only, a higher change in deoxygenated hemoglobin was significantly associated with a higher fat-free mass but not with oxygen uptake-peak.

In those with SMA, higher Fatigue-6MWT correlated with a lower workload peak; higher Fatigue-SME correlated with lower fat-free mass. In controls, fatigue measures were not associated with oxygen uptake-peak, workload peak, or fat-free mass. 

“The results from this study add to the growing body of evidence suggesting that mitochondrial dysfunction contributes to the clinical phenotypes [characteristics] and symptoms experienced by individuals with SMA, including fatigue and reduced exercise capacity,” the scientists concluded. 

“Understanding the subcellular mechanisms underlying diminished muscle oxygen uptake and increased fatigue during exercise in SMA may reveal additional cellular targets for therapeutic intervention,” they added.