Changes in Muscle Fibers and Energy Metabolism Evident in Types 3, 4
The muscle atrophy and weakness characteristic of spinal muscular atrophy (SMA) is aggravated by the loss of fast-contracting white muscle fibers in patients with later-onset disease, an MRI study showed, reportedly for the first time.
Production of the energy molecule ATP was also found to be impaired in white muscle fibers, which may explain why this particular fiber is vulnerable in SMA, leading the researchers to suggest ATP function as a biomarker or target for therapeutics.
The study, “Magnetic resonance reveals mitochondrial dysfunction and muscle remodelling in spinal muscular atrophy,” was published in the journal Brain.
The most common symptoms of SMA include progressive muscle weakness and atrophy (shrinkage) due to the loss of motor neurons — nerve cells that control voluntary muscle movement. Different types of SMA generally follow the age of onset, with types 1 and 2 beginning in infancy, type 3 in early childhood, and type 4 during adulthood.
Beyond motor neuron loss and associated muscle degeneration, animal studies suggest other abnormalities within the muscle itself, such as problems in energy-producing mitochondria, may contribute to disease development and progression.
To test this hypothesis in patients, researchers at the University Medical Centre Utrecht in the Netherlands conducted a detailed investigation of arm muscle structure combined with energetics in patients with type 3 and 4 SMA.
MRI scans as well as phosphorus magnetic resonance spectroscopy (31P MR) — measuring the energy metabolism of muscles — were given to 15 SMA patients (mean age of 40) and 15 healthy age- and gender-matched control participants. Most, 14, had type 3 SMA (four were unable to walk) and one had type 4.
MRI images to view muscle structure focused on the upper arms to examine fat infiltration into the bicep and tricep muscles and muscle atrophy. Consistent with previous MRI images of leg muscles, upper arm images showed fat infiltration and a loss of muscle mass in patients.
Measurements showed that fat content in patients’ biceps and triceps was significantly higher than in controls. Although the cross-sectional area of the tricep muscle was significantly reduced in patients, there were no differences in the cross-sectional area of the biceps between the groups. Higher fat infiltration correlated with the cross-sectional area for both the biceps and triceps.
31P MR spectra data were collected of the biceps and triceps during an arm-cycling exercise to compare with the abundance of red, intermediate, and white muscle fibers (myofibers).
Of note, red muscle fibers contain blood vessels and mitochondria that contract slowly for long periods of time (slow-twitch muscles) without fatigue. In contrast, white muscle fibers have fewer blood vessels and mitochondria, which contract strongly and fast (fast-twitch muscles) but for short periods.
A preliminary test in a healthy person showed a predominantly fast-twitch white muscle fiber characteristic that was consistent with studies of the bicep muscle of healthy adults. In patients, a trend toward a white-to-red shift in tricep muscles was seen compared with controls. In the bicep muscle, this white-to-red shift was significant in patients.
In an additional experiment, patients were four-to-eight times faster to deplete phosphocreatine — a molecule that serves as a rapid reserve of high-energy phosphates to recycle adenosine triphosphate (ATP), the energy currency of the cell.
After the arm-cycling exercise, the resting state of muscle fibers is driven by ATP production in mitochondria from phosphocreatine as well as phosphate.
In controls, the mean recovery time for phosphate to pre-exercise levels in red and intermediate muscle fibers was the same within each muscle but significantly faster in biceps than in triceps. The median recovery time for white muscle fibers was five times slower than red fibers.
In patients, the median phosphate recovery times in red and intermediate muscle fibers of biceps and triceps were the same as controls. But the phosphate recovery time of white muscle fibers in the biceps was almost two times longer than controls. Similar results were found in the tricep muscle in two of four datasets collected in this group.
“These results indicate that mitochondrial ATP synthetic function is compromised in white, but not red or intermediate myofibers of arm muscle in the patient group,” the team wrote. “As a consequence, white fibers of skeletal muscle in this neuromuscular disease are more vulnerable to onset of cellular fatigue mechanisms during physical work.”
Post-exercise phosphocreatine recovery was not prolonged in the biceps and even faster in the triceps of patients than controls, the researchers noted, which “both fit this conclusion and confirm white-to-red muscle remodeling in the patient group,” they added.
Finally, the association between muscle function, structure, and metabolic characteristics in the upper arm of SMA patients was investigated.
A strong correlation between the maximum muscle contraction force and cross-sectional muscle area was found for both biceps and triceps in patients and controls. Notably, in both muscle groups, the contraction force per cross-sectional muscle area was 1.4-time weaker in patients compared with controls.
“Therefore, altered mechanical properties of the muscle itself must also contribute to this decline,” the researchers wrote.
Next, they examined whether a lesser increase in blood lactate levels — produced during intense exercise — would be evident in patients than controls. A strong correlation was found between maximum contraction force and blood lactate changes during exercise in patients for biceps and triceps.
Significant correlations were found for both muscles between blood lactate changes during exercise and 31P MR estimates of intermediate and white myofiber content. Lastly, there was an association between phosphate recovery time in white fibers and white-to-red muscle fiber shift in the biceps muscles of patients. No correlation was found with phosphocreatine.
“This study provides first in vivo [living body] evidence in patients that degeneration of motor neurons and associated musculature causing atrophy and muscle weakness in [SMA] type 3 and 4 is aggravated by disproportionate depletion of myofibers that contract fastest and strongest,” the researchers wrote.
“Our finding of decreased mitochondrial ATP synthetic function selectively in residual white myofibers provides both a possible clue to understanding the apparent vulnerability of this particular fiber type in [SMA] type 3 and 4 as well as a new biomarker and target for therapy,” they added.