Heart problems associated with spinal muscular atrophy (SMA) may be caused partially by calcium dysregulation in heart muscle cells in the absence of the survival motor neuron (SMN) protein, a study suggests.
These findings not only shed light on the underlying mechanisms of heart problems in SMA — which may open new therapeutic avenues — but also support the monitoring of heart function in this patient population.
The study, “SMN-deficiency disrupts SERCA2 expression and intracellular Ca2+ signaling in cardiomyocytes from SMA mice and patient-derived iPSCs,” was published in the journal Skeletal Muscle.
SMA is caused by the loss of SMN, a protein produced in several cell types throughout the body and involved in multiple and fundamental cellular processes. While SMN deficiency in motor nerve cells is considered the disease’s root cause, increasing evidence suggests that other cells and organs in the body also are particularly affected, including the heart.
Cardiovascular problems have been reported in patients with the most severe severe forms of SMA and in mouse models of the disease. Moreover, a previous study supported by the SMA Foundation showed that SMA patients have higher-than-normal levels of several heart failure markers, suggesting that sufficient levels of SMN are essential for normal heart function.
However, the mechanisms behind these SMA-associated heart problems remain largely unknown and no study has established that SMN deficiency directly affects heart function.
Researchers have now evaluated whether SMN deficiency compromised the contractile function of heart cells isolated from a mouse model of a severe form of SMA and also those generated from SMA patients-derived induced pluripotent stem cells (iPSCs).
iPSCs are fully matured cells that researchers can reprogram in a lab dish to revert them back to a stem cell state that has the capacity to differentiate into almost any type of cell.
Results showed that the levels of three heart failure markers — atrial natriuretic peptide, brain natriuretic peptide, and skeletal alpa-actin — were significantly increased in heart tissue from SMA mice prior to considerable neuromuscular degeneration, compared with that from healthy mice.
This suggested that “mechanical function of the heart may be altered early in the disease progression of this severe SMA mouse model,” the researchers wrote.
In agreement, heart cells from SMA mice showed impaired contractile function, compared with cells from healthy mice. The team noted that contraction problems in the heart often are associated with calcium dysregulation and lower levels of SERCA2, an enzyme that controls calcium levels inside cells.
Further analysis showed that SMN-deficient heart cells, from both SMA mice and SMA patients, had a significant drop in SERCA2 levels and impaired calcium dynamics, compared with healthy cells.
Notably, these deficits were at least partially corrected when patient-derived cells were modified to increase their production of SMN protein. Conversely, heart cells derived from healthy individuals and forced to lower their SMN production mimicked the deficits seen in SMN-deficient heart cells.
“These results demonstrate that SMN regulates SERCA2 [levels] and intracellular [calcium dynamics] in [heart cells] that may impair cardiac function and lead to elevation of heart failure markers, as observed in mice … and patients with SMA,” the researchers wrote.
The data also suggest that heart cell dysfunction occurs early in the disease course and therefore is likely to be a direct result of SMN loss and not secondary to neurodegeneration, the team noted.
Since deficits in calcium dynamics also were previously reported to occur in SMN-deficient motor nerve cells, the researchers hypothesized that calcium dysregulation may be a common disease mechanism in SMA.
“Finally, while neuromuscular degeneration remains the hallmark feature of the disease, impaired heart function may be a contributing factor in disease progression that will require monitoring in light of new therapies that are improving motor function and extending survival,” the researchers wrote.
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