CaMKIIβ Signaling drives expression of metabolic and stress response genes in skeletal muscle, and its loss contributes to the LGMDR1 phenotype

Irina Kramerova; Frieda Anastopulos; Diana Becerra; Ruby Goldstein de Salazar; Alexander R Keeble; Jeffrey S Chamberlain; Steven A Moore; Elizabeth M McNally; Melissa J Spencer

doi:10.1093/hmg/ddag090

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CaMKIIβ Signaling drives expression of metabolic and stress response genes in skeletal muscle, and its loss contributes to the LGMDR1 phenotype

Journal article

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Peer reviewed

CaMKIIβ Signaling drives expression of metabolic and stress response genes in skeletal muscle, and its loss contributes to the LGMDR1 phenotype

Irina Kramerova, Frieda Anastopulos, Diana Becerra, Ruby Goldstein de Salazar, Alexander R Keeble, Jeffrey S Chamberlain, Steven A Moore, Elizabeth M McNally and Melissa J Spencer

Human molecular genetics, Vol.35(19), ddag090

09/11/2026

DOI: 10.1093/hmg/ddag090

PMID: 42725915

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Abstract

Calcium calmodulin kinase II (CaMKII) signaling is activated by muscle use and drives gene expression that promotes slow oxidative muscle phenotype. Previously, we showed that the calpain 3 knockout (C3KO) mouse model of limb girdle muscular dystrophy R1 (LGMDR1) exhibits impaired slow-oxidative gene expression and these deficits were associated with reduced levels of the CaMKIIβ isoform and attenuated CaMKII signaling in C3KO muscles. To investigate the contribution of CaMKIIβ signaling to the calpain 3-deficient phenotype, we generated both loss-of-function (muscle-specific conditional knockout, Camk2b cKO) and gain-of-function (muscle-specific overexpression of a constitutively active CaMK2b) models. Camk2b cKO muscles exhibited myopathic features and weakness and their muscles failed to upregulate genes that promote oxidative metabolism and stress-responses following endurance exercise, similarly to C3KO muscles. Mitochondrial respiration showed reduced activity of complex I, complex II and fatty acid oxidation. RNA sequencing of LGMDR1 patient biopsies revealed a similar reduction in genes involved in oxidative metabolism, aligning human and mouse findings. Overexpression of a constitutively active Camk2b in C3KO muscles enhanced oxidative metabolism and improved functional performance. Our results support the hypothesis that blunted CaMKIIβ signaling contributes to the failed upregulation of genes involved in oxidative metabolism and stress-responses in C3KO muscles. These studies highlight metabolic insufficiency as a central contributor to LGMDR1 pathogenesis and support the therapeutic potential of targeting CaMKII signaling to ameliorate disease features in LGMDR1.

Phenotype

Animals

Calcium-Calmodulin-Dependent Protein Kinase Type 2 - genetics

Calcium-Calmodulin-Dependent Protein Kinase Type 2 - metabolism

Calpain - genetics

Calpain - metabolism

Disease Models, Animal

Gene Expression Regulation

Humans

Mice

Mice, Knockout

Muscle Proteins - genetics

Muscle, Skeletal - metabolism

Muscle, Skeletal - pathology

Muscular Dystrophies, Limb-Girdle - genetics

Muscular Dystrophies, Limb-Girdle - metabolism

Muscular Dystrophies, Limb-Girdle - pathology

Oxidative Stress - genetics

Signal Transduction - genetics

Details

Title: Subtitle: CaMKIIβ Signaling drives expression of metabolic and stress response genes in skeletal muscle, and its loss contributes to the LGMDR1 phenotype
Creators: Irina Kramerova - University of California, Los Angeles
Frieda Anastopulos - University of California, Los Angeles
Diana Becerra - University of California, Los Angeles
Ruby Goldstein de Salazar - David Geffen School of Medicine at UCLA
Alexander R Keeble - Northwestern University
Jeffrey S Chamberlain - University of Washington
Steven A Moore - University of Iowa
Elizabeth M McNally - Northwestern University
Melissa J Spencer - University of California, Los Angeles
Resource Type: Journal article
Publication Details: Human molecular genetics, Vol.35(19), ddag090
DOI: 10.1093/hmg/ddag090
PMID: 42725915
NLM abbreviation: Hum Mol Genet
ISSN: 1460-2083
eISSN: 1460-2083
Publisher: Oxford University Press
Grant note: Wellstone Muscular Dystrophy Center: NIH-NIAMS P50 AR052646 NIH-NINDS: R01NS117912 Coalition to Cure Calpain 3
The authors thank Ms J, Wen for excellent technical support. Seahorse analysis was performed by the UCLA Mitochondrial and Metabolism Core and the authors thank Dr Linsey Stiles for advice and consul-tation. This work was supported by a Wellstone Muscular Dystrophy Center grant-NIH-NIAMS P50 AR052646 (to EM and MJS) and by NIH-NINDS R01NS117912 and a grant from the Coalition to Cure Calpain 3 (to MJS and JSC).
Language: English
Date published: 09/11/2026
Academic Unit: Pathology
Record Identifier: 9985224339902771

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