What is the clinical evidence from this study?

Study design: Other. Population: Hypertrophic cardiomyopathy. Intervention: ALPK3 mutation/deficiency vs. Wild-type (WT). Primary outcome: Contractility and sarcomere organization.

What question did this study set out to answer?

This research aims to elucidate the role of alpha kinase 3 (ALPK3) in maintaining sarcomere integrity and proteostasis in striated muscle.

February 15, 2023Nature Cardiovascular ResearchOpen Access

Alpha kinase 3 signaling at the M-band maintains sarcomere integrity and proteostasis in striated muscle

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Key result

ALPK3 deficiency impaired contractility and disrupted sarcomere organization and M-band localization of SQSTM1 in human cardiac organoids and a mouse model.

Why the study?

Pathogenic variants in ALPK3 cause cardiomyopathy and musculoskeletal disease, but little is known about this atypical kinase.

Population

Human cardiac organoids, mice harboring a pathogenic truncating Alpk3 variant, and human pluripotent stem cell-derived cardiomyocytes

Design

Preclinical laboratory study

Authors

JMJames W. McNamaraRoyal Children's Hospital BPBenjamin L. ParkerThe University of Melbourne HVHolly K. VogesRoyal Children's Hospital

Discussion

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Implication

Hypothesis-generating in ALPK3 cardiomyopathy models; leaves open clinical translation and therapeutic targeting.

Key Points

This research aims to elucidate the role of alpha kinase 3 (ALPK3) in maintaining sarcomere integrity and proteostasis in striated muscle.
Defined the ALPK3-dependent phosphoproteome in cardiomyocytes and cardiac organoids.
Analyzed the ALPK3 interactome to confirm binding with M-band proteins.
Used human pluripotent stem cell-derived cardiomyocytes modeling ALPK3 mutations.
ALPK3 deficiency impaired contractility in human cardiac organoids and mouse hearts harboring a pathogenic variant.
ALPK3-dependent phosphopeptides were enriched for M-band components and SQSTM1.
M-band localization of SQSTM1 was abnormal in cardiomyopathic models.

Structured PICO

Population

Experimental study using human pluripotent stem cell-derived cardiomyocytes, human cardiac organoids, and a mouse model to investigate the role of ALPK3 in hypertrophic cardiomyopathy.

Exposure

ALPK3 deficiency / pathogenic truncating Alpk3 variant

Comparator

Wild-type / normal ALPK3 function (implied)

Outcome

Contractility, sarcomeric organization, and M-band localization of SQSTM1surrogate

ALPK3 is an essential component of the sarcomere M-band, and its deficiency impairs contractility and proteostasis, providing a mechanistic basis for ALPK3-related cardiomyopathy.

Limitations

Further studies are required to directly establish whether sarcomeric protein turnover is disrupted due to ALPK3 mutations.
Detailed crystal structure of ALPK3 is needed to define residues regulating catalytic activity.

Cite This Study

McNamara et al. (2023) studied Hypertrophic cardiomyopathy. ALPK3 mutation/deficiency vs. Wild-type (WT) was evaluated on Contractility and sarcomere organization. ALPK3 deficiency impaired contractility and disrupted sarcomere organization and M-band localization of SQSTM1 in human cardiac organoids and a mouse model.

synapsesocial.com/papers/6a5c20dca8b4d22a251e8ec2 https://doi.org/10.1038/s44161-023-00219-9

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Alpha kinase 3 signaling at the M-band maintains sarcomere integrity and proteostasis in striated muscle

Discussion

Member takes

Implication

Key Points

Structured PICO

Limitations

Cite This Study

Alpha kinase 3 signaling at the M-band maintains sarcomere integrity and proteostasis in striated muscle

Discussion

Member takes

Implication

Key Points

Structured PICO

Limitations

Cite This Study

Also Consider

Also Consider