About

Professor James Ervasti, PhD, is affiliated with the Department of Biochemistry, Molecular Biology & Biophysics at the University of Minnesota. His research primarily focuses on fully defining the function of dystrophin in striated muscle to understand how its absence or abnormality leads to the pathologies observed in Duchenne and Becker muscular dystrophies. His approach integrates biochemical and biophysical analyses of the very large dystrophin protein with in vivo assessments of its function in transgenic mouse models of muscular dystrophy. Dr. Ervasti earned his PhD from the University of Minnesota in 1989. His laboratory studies the structure and cellular function of the dystrophin-glycoprotein complex, which spans the muscle cell plasma membrane (sarcolemma) and links the cortical actin cytoskeleton with the extracellular matrix. His work aims to deepen the understanding of the physiological role of this complex, which is crucial for elucidating how its absence or abnormality leads to muscular dystrophies. Dr. Ervasti's contributions include investigating the interactions of dystrophin with other proteins, its effects on actin dynamics, and its role as a microtubule-associated protein, advancing the knowledge of muscle cell biology and muscular dystrophy mechanisms.

Research topics

• Biology
• Internal medicine
• Medicine
• Endocrinology
• Chemistry
• Genetics
• Pharmacology
• Cell biology
• Molecular biology
• Cardiology

Selected publications

• The atomic structure of human dystrophin spectrin-like repeat 24

  Acta Crystallographica Section F Structural Biology Communications · 2026-04-20

  articleOpen access

  The structure of spectrin-like repeat 24 of human dystrophin was determined at 2.5 Å effective resolution. The structure exhibits a three-helix bundle fold, common to all spectrin-repeat family members, and shares a high degree of homology with existing structures of spectrin-like repeat 1 from dystrophin and utrophin. The structure provides molecular details of the atomic interactions that stabilize the repeat, including hydrophobic interactions and inter-helix and intra-helix salt bridges. AlphaFold models of the repeat are in excellent agreement with the structure, showing an all-atom r.m.s.d. of 1.13 Å. Accurate modeling of SR24 supports AlphaFold modeling of all 24 of the dystrophin spectrin-like repeats and the use of these models in predicting the molecular determinants of dystrophin stability, a key aspect of its biological function as a structural protein that cross-links actin filaments to the dystrophin-glycoprotein complex to mediate a mechanical connection between the cytoskeleton and the extracellular matrix.

  PublisherDOI

• Do actin isoforms have unique functionalities at the protein level?

  Nature Communications · 2025-03-07 · 2 citations

  letterOpen access1st authorCorresponding
  PublisherOA PDFDOI

• Human dystrophin tandem calponin homology actin-binding domain crystallized in a closed-state conformation

  Acta Crystallographica Section D Structural Biology · 2025-02-26 · 1 citations

  articleOpen access

  The structure of the N-terminal actin-binding domain of human dystrophin was determined at 1.94 Å resolution. Each chain in the asymmetric unit exists in a `closed' conformation, with the first and second calponin homology (CH) domains directly interacting via a 2500.6 Å 2 interface. The positioning of the individual CH domains is comparable to the domain-swapped dimer seen in previous human dystrophin and utrophin actin-binding domain 1 structures. The CH1 domain is highly similar to the actin-bound utrophin structure and structural homology suggests that the `closed' single-chain conformation opens during actin binding to mitigate steric clashes between CH2 and actin.

  PublisherOA PDFDOI

• The complete absence of cytoplasmic γ‐actin results in no discernible phenotype in mice or primary fibroblasts

  FEBS Journal · 2025-03-20

  articleOpen accessSenior authorCorresponding

  Mice and primary fibroblasts derived from mouse embryos completely lacking cytoplasmic β‐actin, because the Actb gene was engineered to instead express γ‐actin protein, have previously been found to be virtually devoid of phenotype. Here, we report the characterization of mice and mouse embryonic fibroblasts homozygous for an Actg1 allele edited to translate β‐actin instead of γ‐actin ( Actg1‐ coding beta; Actg1 c‐b/c‐b ), which resulted in mice and fibroblasts that are devoid of γ‐actin. We demonstrate that these Actg1 c‐b/c‐b mice present with no measurable phenotype in survival, body mass, activity, muscle contractility, or auditory function. Primary fibroblasts derived from Actg1 c‐b/c‐b mouse embryos were still proliferative, with several measured parameters of cell motility not different from wild type. From these and previous data, we conclude that β‐ and γ‐actin proteins are redundant in primary embryonic fibroblasts and during normal mouse development.

  PublisherOA PDFDOI

• Stress exposure in the <i>mdx</i> mouse model of Duchenne muscular dystrophy provokes a widespread metabolic response

  FEBS Journal · 2025-02-22

  articleOpen accessSenior authorCorresponding

  Duchenne muscular dystrophy is a severe neuromuscular wasting disease that is caused by a primary defect in dystrophin protein and involves organism-wide comorbidities such as cardiomyopathy, metabolic and mitochondrial dysfunction, and nonprogressive cognitive impairments. Physiological stress exposure in the mdx mouse model of Duchenne muscular dystrophy results in phenotypic abnormalities that include locomotor inactivity, hypotension, and increased morbidity. Severe and lethal stress susceptibility in mdx mice corresponds to metabolic dysfunction in several coordinated metabolic pathways within dystrophin-deficient skeletal muscle, as well as prolonged elevation in mdx plasma corticosterone levels that extends beyond the wild-type (WT) stress response. Here, we performed a targeted mass spectrometry-based plasma metabolomics screen focused on biological stress pathways in healthy and dystrophin-deficient mdx mice exposed to mild scruff stress. One-third of the stress-relevant metabolites interrogated displayed significant elevation or depletion in mdx plasma after scruff stress and were restored to WT levels by skeletal muscle-specific dystrophin expression. The metabolic pathways of mdx mice altered by scruff stress are associated with regulation of the hypothalamic-pituitary-adrenal axis, locomotor tone, neurocognitive function, redox metabolism, cellular bioenergetics, and protein catabolism. Our data suggest that a mild stress triggers an exaggerated, multi-system metabolic response in mdx mice.

  PublisherOA PDFDOI

• Proteomics-based evaluation of AAV dystrophin gene therapy outcomes in mdx skeletal muscle

  JCI Insight · 2025-11-27

  articleOpen access

  Duchenne muscular dystrophy (DMD) is a fatal genetic muscle-wasting disease characterized by loss of dystrophin protein. Therapeutic attempts to restore a functional copy of dystrophin to striated muscle are under active development, and many utilize adeno-associated viral (AAV) vectors. However, the limited cargo capacity of AAVs precludes delivery of full-length dystrophin, a 427 kDa protein, to target tissues. Recently, we developed a method to express large dystrophin constructs using the protein trans-splicing mechanism mediated by split inteins and myotropic AAV vectors. The efficacy of this approach to restore muscle function in mdx4cv mice was previously assessed using histology, dystrophin immunolabeling, and Western blotting. Here, we expand our molecular characterization of dystrophin constructs with variable lengths using a mass spectrometry-based proteomics approach, providing insight into unique protein expression profiles in skeletal muscles of wild-type, dystrophic mdx4cv, and AAV-treated mdx4cv mice. Our data reveal several affected cellular processes in mdx4cv skeletal muscles with changes in the expression profiles of key proteins to muscle homeostasis, whereas successful expression of dystrophin constructs results in an intermediate to complete restoration. This study highlights several biomarkers that could be used in future preclinical or clinical studies to evaluate the effectiveness of therapeutic strategies.

  PublisherDOI

• 115PDmd(mdx) and Actb knockout mice share a common redox-dependent mechanism of eccentric contraction-induced force loss rescued by hydrogen sulfide

  Neuromuscular Disorders · 2025-09-01

  articleSenior author
  PublisherDOI

• Mapping SCA1 regional vulnerabilities reveals neural and skeletal muscle contributions to disease

  JCI Insight · 2024-03-21 · 12 citations

  articleOpen access

  Spinocerebellar ataxia type 1 (SCA1) is a fatal neurodegenerative disease caused by an expanded polyglutamine tract in the widely expressed ataxin-1 (ATXN1) protein. To elucidate anatomical regions and cell types that underlie mutant ATXN1-induced disease phenotypes, we developed a floxed conditional knockin mouse (f-ATXN1146Q/2Q) with mouse Atxn1 coding exons replaced by human ATXN1 exons encoding 146 glutamines. f-ATXN1146Q/2Q mice manifested SCA1-like phenotypes including motor and cognitive deficits, wasting, and decreased survival. Central nervous system (CNS) contributions to disease were revealed using f-ATXN1146Q/2Q;Nestin-Cre mice, which showed improved rotarod, open field, and Barnes maze performance by 6-12 weeks of age. In contrast, striatal contributions to motor deficits using f-ATXN1146Q/2Q;Rgs9-Cre mice revealed that mice lacking ATXN1146Q/2Q in striatal medium-spiny neurons showed a trending improvement in rotarod performance at 30 weeks of age. Surprisingly, a prominent role for muscle contributions to disease was revealed in f-ATXN1146Q/2Q;ACTA1-Cre mice based on their recovery from kyphosis and absence of muscle pathology. Collectively, data from the targeted conditional deletion of the expanded allele demonstrated CNS and peripheral contributions to disease and highlighted the need to consider muscle in addition to the brain for optimal SCA1 therapeutics.

  PublisherOA PDFDOI

• Two operational modes of atomic force microscopy reveal similar mechanical properties for homologous regions of dystrophin and utrophin

  bioRxiv (Cold Spring Harbor Laboratory) · 2024-05-20 · 1 citations

  preprintOpen access

  Duchenne muscular dystrophy (DMD) is a lethal muscle disease caused by the absence of the protein dystrophin. Dystrophin is hypothesized to work as a molecular shock absorber that limits myofiber membrane damage when undergoing reversible unfolding upon muscle stretching and contraction. Utrophin is a dystrophin homologue that is under investigation as a protein replacement therapy for DMD. However, it remains uncertain whether utrophin can mechanically substitute for dystrophin. Here, we compared the mechanical properties of homologous utrophin and dystrophin fragments encoding the N terminus through spectrin repeat 3 (UtrN-R3, DysN-R3) using two operational modes of atomic force microscopy (AFM), constant speed and constant force. Our comprehensive data, including the statistics of force magnitude at which the folded domains unfold in constant speed mode and the time of unfolding statistics in constant force mode, show consistent results. We recover parameters of the energy landscape of the domains and conducted Monte Carlo simulations which corroborate the conclusions drawn from experimental data. Our results confirm that UtrN-R3 expressed in bacteria exhibits significantly lower mechanical stiffness compared to insect UtrN-R3, while the mechanical stiffness of the homologous region of dystrophin (DysN-R3) is intermediate between bacterial and insect UtrN-R3, showing greater similarity to bacterial UtrN-R3. Significance Duchenne muscular dystrophy (DMD) is a severe muscle wasting disorder caused by mutations in DMD gene encoding dystrophin. Utrophin, a fetal homologue of dystrophin, is under active investigation as a dystrophin replacement therapy for DMD. However, it is still unknown if it can substitute dystrophin mechanically. Here, we report mechanical properties of both utrophin and dystrophin fragments encoding the N terminus through spectrin repeat 3 (UtrN-R3, DysN-R3) using atomic force microscope (AFM) through two operational modes, constant speed and constant force. Our data, consistent across both modes, confirm that UtrN-R3 expressed in bacteria exhibits significantly lower mechanical stiffness than insect UtrN-R3. Additionally, bacterial DysN-R3 lies between bacterial and insect UtrN-R3 in terms of mechanical properties, leaning closer to bacterial UtrN-R3.

  PublisherOA PDFDOI

• Author response for "Stress exposure in the &lt;i&gt;mdx&lt;/i&gt; mouse model of Duchenne muscular dystrophy provokes a widespread metabolic response"

  2024-12-13

  peer-reviewSenior author
  PublisherDOI

Recent grants

• Costamere Defects in Muscular Dystrophies

  NIH · $7.6M · 2005–2026

• Minnesota Muscle Training Program

  NIH · $9.0M · 2001–2027

• NIH Grant K02AR001985

  NIH · $415k · 2001

• Cytoskeletal Interactions of Dystrophin

  NIH · $9.3M · 1994–2026

Frequent coauthors

• Kevin P. Campbell

  University of Florida

  37 shared

• Dawn A. Lowe

  University of Minnesota

  28 shared

• Angus Lindsay

  University of Minnesota

  25 shared

• Benjamin J. Perrin

  Indiana University – Purdue University Indianapolis

  19 shared

• Kay Ohlendieck

  National University of Ireland, Maynooth

  19 shared

• Steven D. Kahl

  Eli Lilly (United States)

  19 shared

• Joseph J. Belanto

  University of Minnesota

  15 shared

• Inna N. Rybakova

  University of Wisconsin–Madison

  14 shared