About

Henk Granzier is a Professor in the Department of Cellular and Molecular Medicine at the University of Arizona. His professional profile is listed under the Biochemistry and Molecular & Cellular Biology Graduate Program. The page does not provide specific details about his research focus, background, or key contributions.

Research topics

• Medicine
• Biology
• Cell biology
• Internal medicine
• Endocrinology
• Cardiology
• Computer Science
• Biochemistry
• Genetics
• Molecular biology
• Pathology
• Chemistry
• Pharmacology
• Intensive care medicine

Selected publications

• Quantitative sex-specific analysis of disease-associated elements of ventricular myocyte remodeling in an obese-diabetic murine model of HFpEF

  Journal of Molecular and Cellular Cardiology Plus · 2026-03-01

  articleOpen access
  PublisherDOI

• Discovery of Titin and Its Role in Heart Function and Disease

  Circulation Research · 2025-01-02 · 29 citations

  review1st authorCorresponding

  This review examines the giant elastic protein titin and its critical roles in heart function, both in health and disease, as discovered since its identification nearly 50 years ago. Encoded by the TTN (titin gene), titin has emerged as a major disease locus for cardiac disorders. Functionally, titin acts as a third myofilament type, connecting sarcomeric Z-disks and M-bands, and regulating myocardial passive stiffness and stretch sensing. Its I-band segment, which includes the N2B element and the PEVK (proline, glutamate, valine, and lysine-rich regions), serves as a viscoelastic spring, adjusting sarcomere length and force in response to cardiac stretch. The review details how alternative splicing of titin pre-mRNA produces different isoforms that greatly impact passive tension and cardiac function, under physiological and pathological conditions. Key posttranslational modifications, especially phosphorylation, play crucial roles in adjusting titin’s stiffness, allowing for rapid adaptation to changing hemodynamic demands. Abnormal titin modifications and dysregulation of isoforms are linked to cardiac diseases such as heart failure with preserved ejection fraction, where increased stiffness impairs diastolic function. In addition, the review discusses the importance of the A-band region of titin in setting thick filament length and enhancing Ca² + sensitivity, contributing to the Frank-Starling Mechanism of the heart. TTN truncating variants are frequently associated with dilated cardiomyopathy, and the review outlines potential disease mechanisms, including haploinsufficiency, sarcomere disarray, and altered thick filament regulation. Variants in TTN have also been linked to conditions such as peripartum cardiomyopathy and chemotherapy-induced cardiomyopathy. Therapeutic avenues are explored, including targeting splicing factors such as RBM20 (RNA binding motif protein 20) to adjust isoform ratios or using engineered heart tissues to study disease mechanisms. Advances in genetic engineering, including CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats), offer promise for modifying TTN to treat titin-related cardiomyopathies. This comprehensive review highlights titin’s structural, mechanical, and signaling roles in heart function and the impact of TTN mutations on cardiac diseases.

  PublisherDOI

• BPS2025 - Deleting a single titin A-band domain (A109) alters thick filament structure and function in striated muscle

  Biophysical Journal · 2025-02-01

  articleSenior author
  PublisherDOI

• The titin N2A-MARP signalosome constrains muscle longitudinal hypertrophy in response to stretch

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-06-25 · 1 citations

  preprintOpen access

  Titin-based mechanosensing is a key driver of trophic signaling in muscle, yet the downstream pathways linking titin sensing to muscle remodeling remain poorly understood. To investigate these signaling mechanisms, we utilized unilateral diaphragm denervation (UDD), an in vivo model that induces titin-stiffness-dependent hypertrophy via mechanical stretch. Using UDD in rats and mice, we characterized the longitudinal hypertrophic response and distinguished stretch-induced signaling from denervation effects by performing global transcriptomic and proteomic analyses following UDD and bilateral diaphragm denervation (BDD) in rats. Our findings identified upregulation of titin-associated muscle ankyrin repeat proteins (MARPs). Subsequent phosphorylation enrichment mass spectrometry in mouse diaphragm highlighted the involvement of the N2A-element. UDD in MARP knockout (KO) mice resulted in enhanced longitudinal hypertrophy, with Western blot analysis revealing activation of the mTOR pathway. Furthermore, pharmacological inhibition of mTORC1 with rapamycin suppressed longitudinal hypertrophy, demonstrating that mTOR signaling regulates titin-mediated hypertrophic growth in a MARP-dependent manner. These findings establish MARPs as key modulators of titin-based mechanotransduction and highlight mTORC1 as a central regulator of longitudinal muscle hypertrophy.

  PublisherOA PDFDOI

• Glycerol storage increases passive stiffness of muscle fibers through effects on titin extensibility

  The Journal of General Physiology · 2025-05-09 · 7 citations

  articleOpen accessSenior author

  To study the physiological and pathological mechanisms of muscle, it is crucial to store muscle samples in ways that preserve their properties. Glycerol is commonly used for storage, as it stabilizes muscle proteins, slows enzymatic activity, and minimizes degradation. However, previous studies validating glycerol storage have not examined its effects on passive properties. In this study, mouse extensor digitorum longus (EDL) muscles were stored in 50% glycerol in relaxing solution with protease inhibitors for various durations, then rehydrated in physiological solutions to assess mechanical properties. Active properties remained unchanged, but passive stress was sensitive to glycerol storage, showing a 56.5 ± 13.6% increase after 4 days, and this effect was permanent. The increase was most pronounced at sarcomere lengths, where titin's PEVK segment extension dominates. Using gelsolin, we determined whether the passive stress increase requires the thin filament, which is known to interact with titin's PEVK region. Both glycerol-stored fibers with and without thin filament extraction exhibited increased passive stress, suggesting that the underlying mechanism is intrinsic to titin. Finally, fibers treated with methylglyoxal, a reactive carbonyl and glycating agent that forms cross-links on lysine residues, showed a significant increase in passive stress in fibers stored in relaxing solution but not in glycerol. Thus, glycerol storage elevates passive stress in a titin-specific manner, likely involving lysine residues in the PEVK. Therefore, glycerol storage should be avoided when assessing passive stiffness. We further showed that, for long-term preservation, storage of rapidly frozen muscle at -80°C is a viable option.

  PublisherDOI

• Rbm20 antisense oligonucleotides alleviate diastolic dysfunction in a mouse model of cardiometabolic heart failure (HFpEF)

  Cardiovascular Research · 2025-09-23 · 3 citations

  articleOpen access

  AIMS: Heart failure with preserved ejection fraction (HFpEF) is prevalent, deadly, and difficult to treat. Risk factors such as obesity and hypertension contribute to cardiac inflammation, metabolic defects, and pathological remodelling that impair ventricular filling in diastole. Titin based stiffness is a main determinant of diastolic function and can be adjusted by the splicing regulator RNA binding motif protein 20 (RBM20). Inhibition of RBM20 using antisense oligonucleotides (ASOs) induces expression of compliant titin isoforms, which reduce stiffness. However, dose finding and documenting utility in primarily cardiometabolic disease remains challenging. METHODS AND RESULTS: Here, we optimized RBM20-ASO dosing in a HFpEF mouse model that closely mimics human disease, characterized by metabolic syndrome and comorbidities, but without primary defects in titin or RBM20. Partial inhibition of RBM20 (∼50%) selectively increased compliant titin isoforms, improving diastolic function while preserving systolic performance. This intervention reduced left ventricular stiffness, enhanced relaxation, and mitigated cardiac hypertrophy, despite ongoing systemic comorbidities. CONCLUSION: Our findings demonstrate that targeting titin stiffness with Rbm20-ASOs can serve as an alternative or adjunctive therapeutic strategy for HFpEF to restore cardiac function and prevent further organ damage. The approach may offer benefits even in the presence of phenotypic heterogeneity and unresolved systemic comorbidities.

  PublisherDOI

• Generation of a novel mouse model of nemaline myopathy due to recurrent NEB exon 55 deletion

  Skeletal Muscle · 2025-03-19

  articleOpen access

  was developed; however, it presented an uncharacteristically severe phenotype with a near complete reduction in Neb transcript expression that is not observed in NEB exon 55 patients. We identified by RNA sequencing that the cause of this unexpectedly severe presentation in mice is the generation of a pseudoexon containing two premature termination codons (and promoting nonsense mediated decay) at the Neb exon 55 deletion site. To prove that this is the cause of the loss of Neb transcript, and to generate a more faithful model of the human disease, we used CRISPR gene editing to remove the pseudoexon sequence and replace it with human intron 54 sequence containing a validated cas9 gRNA protospacer. The resulting "hmz" mice have a significant reduction in pseudoexon formation (93.6% reduction), and a re-introduction of stable Neb transcript expression. This new model has the characteristic features of nemaline myopathy at the physiological, histological, and molecular levels. Importantly, unlike the existing exon 55 deletion mice (which die by age 7 days), it survives beyond the first months and exhibits obvious signs of neuromuscular dysfunction. It thus provides a new, robust model for studying pathomechanisms and developing therapies for NEB related nemaline myopathy.

  PublisherOA PDFDOI

• An ovary-intact postmenopausal HFpEF mouse model; menopause is more than just estrogen deficiency

  American Journal of Physiology-Heart and Circulatory Physiology · 2025-02-18 · 6 citations

  articleOpen accessSenior author

  Although ovariectomized mice were observed to be resistant to developing HFpEF, ovary-intact postmenopausal mice exhibited an HFpEF-like phenotype under metabolic stress conditions. The increased susceptibility of ovary-intact postmenopausal mice may be due to relative androgen excess conditions, as postmenopausal ovaries retain the ability to secrete androgens. Menopause should be viewed as the imbalance of estrogen and androgens rather than merely an estrogen deficiency, and the role of female androgens in postmenopausal HFpEF warrants further investigation.

  PublisherDOI

• Abstract Wed043: Genetic Variants in RNA Binding Motif Protein 20 Cause Early-onset Heart Failure by Disrupting Post-Transcriptional Process

  Circulation Research · 2025-08-01

  article

  Introduction: RNA binding motif protein 20 (RBM20) cardiomyopathy is a severe form of dilated cardiomyopathy (DCM), leading to early-onset heart failure (HF). The condition has been linked to cytoplasmic RBM20 granules induced by RBM20 genetic variants, although the precise mechanism remains unclear. Methods: We identified the protein components of RBM20 granules using proximity labeling proteomics analysis. TurboID biotin ligase was fused to wild-type (WT) or Rbm20 with a S640G variant ( Rbm20 S640G ) and transfected into H9c2 cells, followed by biotin treatment. Biotinylated proteins were captured using streptavidin and analyzed with mass spectrometry. Identified proteins were validated by co-immunofluorescence (Co-IF) and co-immunoprecipitation (Co-IP). RT-PCR was performed to assess gene splicing. Anti-Rbm20 antisense oligonucleotides (ASOs) were administered to Rbm20 S639G knock-in mice to inhibit Rbm20 expression. Results: Proximity labeling identified 32 proteins in nuclear and 13 proteins in cytoplasmic RBM20 granules. Gene ontology analysis revealed that nuclear granule proteins were primarily involved in splicing and transcriptional regulation, while cytoplasm granule proteins were associated with cytoplasmic granule assembly. Notably, two RNA binding proteins (RBPs), CELF1 and MBNL2, were found in both nuclear and cytoplasmic RBM20 granules, as confirmed by Co-IF and Co-IP, suggesting their sequestration in cytoplasmic granules. RT-PCR analysis demonstrated mis-splicing of CELF and MBNL target genes in the heart muscle of Rbm20 S639G mice, but not in Rbm20 knockout mice. Importantly, disassembly of cytoplasmic RBM20 granules via ASO treatment alleviated cardiac function and mitigated disease severity. Conclusion: Our findings suggest that cytoplasmic RBM20 granules sequester essential RBPs, leading to abnormal post-transcriptional regulation, which may contribute to the pathogenesis of severe DCM and HF. Targeting and disassembling cytoplasmic RBM20 granules presents a promising therapeutic approach for alleviating disease progression.

  PublisherDOI

• Reducing Granules Without Splicing Restoration Alleviates RBM20 Cardiomyopathy

  Circulation Research · 2025-04-17 · 8 citations

  articleOpen access

  BACKGROUND: RBM20 (RNA binding motif protein 20) cardiomyopathy is a severe form of dilated cardiomyopathy (DCM). Genetic variants in the nuclear localization signal of Rbm20 hinder its nuclear import and promote cytoplasmic pathogenic RNP (ribonucleoprotein) granules. We aimed to investigate whether reducing RNP granules by inhibiting Rbm20 expression could alleviate the DCM phenotype in Rbm20 S639G ( Rbm20 S639G ) knock-in mice. METHODS: We downregulated Rbm20 , utilizing antisense oligonucleotides (ASOs) that specifically inhibit Rbm20 expression. We administered Rbm20 -ASOs in Rbm20 S639G mice that carry a serine-to-glycine substitution in the nuclear localization signal of RBM20. The Rbm20 -ASOs were administered subcutaneously at 25 mg/kg once a week for 8 weeks in both young (14-day-old) mice before the onset of DCM and adult (3-month-old) mice with established DCM phenotype. In vivo cardiac function was assessed by echocardiography. RNP granules were identified through fluorescent immunohistochemical staining, and the number and size of RNP granules were quantified using Cell Profiler software. Alternative splicing of RBM20 target genes was determined by reverse transcription polymerase chain reaction, and titin isoform expression was analyzed by gel electrophoresis. Cardiomyocyte Ca 2+ release-reuptake kinetics and mouse electrocardiography were also studied. RESULTS: The results revealed that reducing the level of Rbm20 expression through treatment with ASOs significantly decreased the cytoplasmic RNP granules within the Rbm20 S639G cardiomyocytes. ASO treatment reduced the severity of DCM developed when treatment was initiated before the onset of the disease. Importantly, ASO treatment reversed cardiac dysfunction and remodeling when treatment was commenced in mice with established DCM as shown by a significant improvement in ejection fraction and a decrease in the severity of left ventricular chamber dilation. Treatment with ASOs also effectively mitigated left ventricular hypertrophic remodeling and improved ECG parameters observed as normalized P wave and QRS durations. These beneficial effects occur without the restoration of mis-splicing of RBM20 target genes, including the primary target gene Ttn , and other genes such as Camk2d , Ryr2 , and Ank3 . CONCLUSIONS: The findings of this study demonstrated that RNP granules serve as a critical driver for RBM20 cardiomyopathy, and reduction of RNP granules through treatment with ASOs is a possible therapeutic option for RBM20 cardiomyopathy in patients carrying RBM20 genetic variants in the nuclear localization signal region.

  PublisherOA PDFDOI

Recent grants

• Function of Giant Sarcomere Matrix Proteins in Muscle

  NIH · $6.6M · 1995–2021

• NIH Grant R01HL067274

  NIH · $1.0M · 2006

• NIH Grant R01AR060697

  NIH · $1.7M · 2017

• NIH Grant R01HL084579

  NIH · $1.9M · 2013

• NIH Grant R01HL118524

  NIH · $2.5M · 2019

Frequent coauthors

• Siegfried Labeit

  350 shared

• Carlos Hidalgo

  University of Arizona

  294 shared

• Coen A. C. Ottenheijm

  Amsterdam University Medical Centers

  236 shared

• Alan H. Beggs

  229 shared

• Michael W. Lawlor

  214 shared

• Lindsay C. Swanson

  Boston Children's Hospital

  205 shared

• Jocelyn Laporte

  Inserm

  198 shared

• Elizabeth T. DeChene

  Children's Hospital of Philadelphia

  198 shared