PREreview of p38β/MAPK11 Deficiency Exacerbates Cardiac Structural and Electrophysiological Remodeling and Contributes to Immune Dysregulation in the Aging Heart

P38β /MAPK11 Deficiency Exacerbates Cardiac Structural and Electrophysiological Remodeling and Contributes to Immune Dysregulation in the Aging Heart.

Trampel et al, 2026

In this work, Trampel at al pose p38β/MAPK11 as a potential regulator to age-related structural and electrophysiological remodeling. p38β is an isoform of the mitogen-activated protein kinase (MAPK) family. The authors describe these as crucial regulators of adaptive and maladaptive stress responses in the aging heart and offer a broad characterization of the middle-aged cardiac phenotype of the germline p38β^-/- mouse. Using an in-vivo and ex-vivo tests of cardiac structure and function, combined with molecular biology and transcriptomic profiling, they examined how the loss of this cardiac stress response regulator influences the onset of fibrosis, arrhythmia and changes in the immune microenvironment. Their results suggest p38β plays a key role in maintaining homeostasis in the aging heart. However, the targets of phosphorylation and how phosphorylation of proteins by p38β is involved in homeostatic regulation is not introduced. This leaves out the greater context of why this protein may be critically involved in maintaining cardiac structure and function in age. This work best fits in the broader context of understanding what role mitogen-activated protein kinases may play in regulating cardiovascular function and the progression of age-related cardiovascular diseases.

Major Points:

1. Age-related or inherent phenotype of p38β knockout?

For all experiments in the present study, aged p38β^-/- mice are compared to age-matched WT control mice. The authors claim the p38β^-/- animals have an apparent age-related loss of cardiovascular fitness and associated inflammatory microenvironment profile. Critically, as there is no inclusion of a young p38β^-/- group, there is little evidence to prove p38β is sufficient to protect the heart from structural and electrical remodeling and immune dysregulation over a lifespan. It remains unclear whether this phenotype is truly age-related in the knockout mice or this is a developmental phenotype associated with the loss of a critical regulatory protein. In including a young cohort of p38β^-/- mice, a stronger claim may be that p38β is sufficient to prevent age-related deterioration in cardiac function. Alternatively, if the cardiac function of young p38β^-/- has been previously established by the group or others, this point may mentioned and cited.

2. Broad age-range used in study

Authors utilize animals across a 6.5-month span of ages, 13.5 to 20 months. This age range overlaps with what is considered both middle-aged (10-15 months) and old age (18-24 months), per the Jackson Laboratory aging standard. This prompts a confusing definition of what ‘aged’ means in the context of this study. For only the electrocardiogram experiments, middle-aged (undefined age range, Figure 2) and advanced-aged (20 months, supplementary figure) were investigated separately. While the advanced-aged p38β^-/- mice exhibit prolonged QT and QTc intervals, there is also an elongation of the QRS duration that is not addressed. This change in phenotype requires deeper evaluation, especially as only female mice were investigated at this advanced age. In the discussion, authors defend the middle age range for the onset of cardiac dysfunction, making it a relevant period to study. It remains unclear for each experiment if all mice included in the analysis fell within the age range described here by the authors. For each experiment described in the methods section, include the range and average age for the mice included.

3. [1] Suggestions for statistical methods of sex-stratification

Differences between aged male and female p38β^-/- and WT mice were explored across experiments. The Statistical Analysis methods section states Student’s t-test were used for comparisons between two independent groups were used, and one-way ANOVA for comparisons among two or more groups. It is unclear through the supplemental table legends which statistical test was used to determine sex differences between groups, as only p<0.05 is stated. To test if there is an effect of sex on the outcome variable between p38β^-/- and WT mice, a two-way ANOVA would be more appropriate.

4. Unable to interpret methods used in pacing experiments

There is a large but insignificant difference in the % EAD Incidence between WT and p38β^-/- mice (~20% and 65%). This suggests potentially a large variation in the data that is unable to be interpreted by the readers due to the lack of error bars in panel H. Further, there is not a clear description of how pacing experiments were performed and there is variation in the times the paces were delivered between WT and p38β^-/- hearts. Representative traces of OAP under both pacing conditions (~150 ms and ~425 ms) are required for WT and p38β^-/- hearts with a clear % EAD for each condition.

Minor points:

1. p38β^-/- mice have a notable increase in stroke volume (Fig1I) as measured with echocardiography, however there is no change in cardiac output (Fig1J). Cardiac output is a measure of stroke volume and heart rate. This suggests that there is a slowed heart rate associated with p38β^-/- deficiency. Including heart rate measurements in the echocardiography and electrophysiology measurements would improve the interpretation of this finding.

2. In vivo ECGs show a slowed QT and QT_c interval in p38β^-/- mice compared to WT, suggesting depressed ventricular repolarization. This phenotype is not recapitulated in the ex-vivo heart as measured by optical action potentials. The authors suggest the influence of autonomic tone in vivo having potential influence on this discrepancy. This theory may be tested using an autonomic block or calculation of heart rate variability in vivo.

3. The figure legend for Figure 5 does not match the panels presents. Panels B-E correspond with the representative recordings described in the legend as A-D. Panel F and G in the figure are described as E and F in the legend. Panels H-J in the figure are described out of order as G,H and I.

4. Figure 9 investigates the skeletal remodeling of p38β^-/- and p38β^+/- mice compared against age-matched WT mice. Authors make the connection that osteoporosis and cardiovascular disease are linked through shared risk factors and chronic inflammation to emphasize the point that p38β serves as a regulator of multiple organ systems. While these points are fair, this experiment does not largely support the scope of the paper and seems misplaced as the penultimate figure of a paper investigating cardiovascular aging. This figure would be better suited as a supplement to show the global phenotype of p38β deficiency.

I am one of 2 participants from the same research lab that reviewed this preprint as part of the Transparent and Accountable Peer Review training program. This report was written with the support of my research mentor.

Competing interests

The authors declare that they have no competing interests.

Use of Artificial Intelligence (AI)

The authors declare that they did not use generative AI to come up with new ideas for their review.