Abstract
Mutations in CAPN3 cause autosomal recessive limb girdle muscular dystrophy 2A. Calpain 3 (CAPN3) is a calcium dependent protease residing in the myofibrillar, cytosolic and triad fractions of skeletal muscle. At the triad, it colocalizes with calcium calmodulin kinase IIβ (CaMKIIβ). CAPN3 knock out mice (C3KO) show reduced triad integrity and blunted CaMKIIβ signaling, which correlates with impaired transcriptional activation of myofibrillar and oxidative metabolism genes in response to running exercise. These data suggest a role for CAPN3 and CaMKIIβ in gene regulation that takes place during adaptation to endurance exercise. To assess whether CAPN3- CaMKIIβ signaling influences skeletal muscle remodeling in other contexts, we subjected C3KO and wild type mice to hindlimb unloading and reloading and assessed CaMKIIβ signaling and gene expression by RNA-sequencing. After induced atrophy followed by 4 days of reloading, both CaMKIIβ activation and expression of inflammatory and cellular stress genes were increased. C3KO muscles failed to activate CaMKIIβ signaling, did not activate the same pattern of gene expression and demonstrated impaired growth at 4 days of reloading. Moreover, C3KO muscles failed to activate inducible HSP70, which was previously shown to be indispensible for the inflammatory response needed to promote muscle recovery. Likewise, C3KO showed diminished immune cell infiltration and decreased expression of pro-myogenic genes. These data support a role for CaMKIIβ signaling in induction of HSP70 and promotion of the inflammatory response during muscle growth and remodeling that occurs after atrophy, suggesting that CaMKIIβ regulates remodeling in multiple contexts: endurance exercise and growth after atrophy.
Highlights
Limb girdle muscular dystrophy 2A (LGMD2A) is an autosomal recessive, progressive muscle-wasting disorder and is one of the most prevalent forms of LGMD, accounting for 30% of all LGMDs [1]
We previously showed that calpain 3 (CAPN3)/calmodulin kinase IIb (CaMKIIb) signaling is one such pathway that is activated after running exercise and this signaling is blunted in CAPN3 knock out mice (C3KO) muscles, compromising their ability to adapt and switch to a more oxidative phenotype [8,9]
These results led to the hypothesis that the triad protein complex, that includes CAPN3, and CaMKIIb may act as a sensor of environmental cues that trigger muscle adaptation
Summary
Limb girdle muscular dystrophy 2A (LGMD2A) is an autosomal recessive, progressive muscle-wasting disorder and is one of the most prevalent forms of LGMD, accounting for 30% of all LGMDs [1]. CAPN3 is a member of a larger family of calcium dependent proteases, but CAPN3 is unique in that it is primarily restricted to skeletal muscle [3]. At this time, CAPN3’s role in muscle and the underlying reason for why loss of function mutations cause LGMD2A is still not well understood. CAPN3 deficient muscles preserve normal sarcolemmal integrity even following a period of exercise [4,5]. The strong sarcolemmal integrity in this disease distinguishes it from the dystrophinopathies and suggests an altogether different pathomechanism of disease
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