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August 5, 2026The Journal of General PhysiologyOpen Access

Diastolic contributors in cardiomyocytes of a cardiometabolic HFpEF-like mouse model

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Why the study?

The relative contributions of passive sarcomere stiffness, microtubules, and diastolic crossbridges to cardiomyocyte diastolic stiffness in HFpEF conditions were unclear.

Population

Intact cardiomyocytes isolated from two-hit cardiometabolic HFpEF-like mice of both sexes

Comparison

XB inhibitor, colchicine, or combined treatment vs baseline

Design

Preclinical experimental study

Key result

Male HFpEF-like cardiomyocytes exhibited increases in passive sarcomere stress (by 70%) and diastolic crossbridges (by 52%), whereas female cardiomyocytes showed an increase in passive sarcomere stress alone (by 55%).

Authors

ASArooj ShahidTMTimothy S. McMillenSDSamuel Daugherty

Discussion

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Overview

Animal models identify diastolic stiffness contributors in HFpEF; leaves open clinical translation and therapeutic targeting.

Key Points

  • To determine the sex-specific relative contributions of passive sarcomere stress, microtubules, and diastolic crossbridge activity to cardiomyocyte stiffness in cardiometabolic HFpEF.
  • Isolated intact cardiomyocytes from male and female two-hit cardiometabolic HFpEF-like mice.
  • Used a stretch-release protocol alongside colchicine and crossbridge inhibitor treatments to separate passive sarcomere stress, microtubule contributions, and diastolic crossbridge activity.
  • Male HFpEF-like cardiomyocytes exhibited increases in both passive sarcomere stress (by 70%) and diastolic crossbridges (by 52%), with elevated crossbridge activity linked to microtubule networking and altered calcium transients.
  • Female HFpEF-like cardiomyocytes showed an isolated 55% increase in passive sarcomere stress, without an elevation in diastolic crossbridge activity.

Structured PICO

P
Population
Intact cardiomyocytes isolated from male and female two-hit mice, a cardiometabolic HFpEF-like model.
I
Intervention
Crossbridge (XB) inhibitor and colchicine treatment
C
Comparator
Untreated cells / baseline state
O
Outcome
Relative contributions of passive sarcomere stress, the microtubule network, and diastolic XB activity to overall diastolic stresssurrogate

Sex differences exist in the mechanisms of cardiomyocyte diastolic stiffness in a cardiometabolic HFpEF-like mouse model, with males showing increased passive sarcomere stiffness and diastolic crossbridge activity, while females show only increased passive sarcomere stiffness.

Cite This Study

Shahid et al. (2026) studied HFpEF-like mouse model. XB inhibitor and colchicine treatment was evaluated on Relative contributions of passive sarcomere stress, the microtubule network, and diastolic XB activity to overall diastolic stress. Male HFpEF-like cardiomyocytes exhibited increases in passive sarcomere stress (by 70%) and diastolic crossbridges (by 52%), whereas female cardiomyocytes showed an increase in passive sarcomere stress alone (by 55%).

synapsesocial.com/papers/6a8feebbf8eca73c40040e2fhttps://doi.org/10.1085/jgp.202614028
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