{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T13:11:14Z","timestamp":1789132274661,"version":"build-2803163510"},"reference-count":49,"publisher":"Oxford University Press (OUP)","issue":"19","license":[{"start":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T00:00:00Z","timestamp":1789084800000},"content-version":"vor","delay-in-days":253,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,9,11]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>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 CaMKII\u03b2 isoform and attenuated CaMKII signaling in C3KO muscles. To investigate the contribution of CaMKII\u03b2 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 CaMKII\u03b2 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.<\/jats:p>","DOI":"10.1093\/hmg\/ddag090","type":"journal-article","created":{"date-parts":[[2026,9,4]],"date-time":"2026-09-04T11:29:36Z","timestamp":1788521376000},"source":"Crossref","is-referenced-by-count":0,"title":["CaMKII\u03b2 Signaling drives expression of metabolic and stress response genes in skeletal muscle, and its loss contributes to the LGMDR1 phenotype"],"prefix":"10.1093","volume":"35","author":[{"given":"Irina","family":"Kramerova","sequence":"first","affiliation":[{"name":"Department of Neurology, David Geffen School of Medicine at UCLA, University of California , 635 Charles E. 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