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Disruption of STIM1-mediated Ca2+ sensing and energy metabolism in adult skeletal muscle compromises exercise tolerance, proteostasis and lean mass

ABSTRACT: STIM1 is a single-pass transmembrane endoplasmic/sarcoplasmic reticulum (E/SR) protein recognized for its role in store operated Ca2+ entry (SOCE), an ancient and ubiquitous signaling pathway. Whereas STIM1 is indispensable during development, its biological and metabolic functions in mature muscle were unclear. Shown here, STIM1 is abundant in adult skeletal muscle, upregulated by exercise, and present at SR-mitochondria interfaces. Among its multifaceted roles, STIM1 regulates Ca2+ signaling, mitochondrial Ca2+ loading, energy metabolism and protein homeostasis. Thus, inducible tissue-specific deletion of STIM1 (iSTIM1 KO) in adult muscle leads to diminished lean mass, reduced exercise capacity, and perturbed fuel selection in settings of energetic stress, without affecting whole-body glucose tolerance. Proteomics and phospho-proteomics analyses of iSTIM1 KO muscles revealed molecular signatures of low-grade E/SR stress and broad activation of processes and signaling networks involved in proteostasis. The findings provide insight into the pathophysiology of muscle diseases linked to disturbances in STIM1-dependent calcium handling.

ORGANISM(S): Mus Musculus (mouse)

SUBMITTER: Deborah Muoio

PROVIDER: PXD030674 | JPOST Repository | Thu Dec 30 00:00:00 GMT 2021

REPOSITORIES: jPOST

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Project description:Protein function is controlled by the cellular proteostasis network. Proteostasis is energetically costly and those costs must be balanced with the energy needs of other physiological functions. Hypertonic stress causes widespread protein damage in C. elegans. Suppression and management of protein damage is essential for optimal survival under hypertonic conditions. ASH chemosensory neurons allow C. elegans to detect and avoid strongly hypertonic environments. We demonstrate that gene mutations that disrupt ASH mediated hypertonic avoidance behavior or genetic ablation of ASH neurons enhance survival during hypertonic stress. Enhanced survival is not due to altered systemic volume homeostasis or organic osmolyte accumulation. Instead, loss of ASH neuron function reduces protein damage in non-neuronal cells. Improved proteostasis capacity is due in part to upregulation of genes that play important roles in managing protein damage. We propose that inhibitory signaling from ASH neurons normally suppresses expression of genes required for non-neuronal cell proteostasis. Because all cells have the capacity to sense and respond to stressors, inhibitory neuronal signaling may be important for minimizing activation of cellular stress resistance and proteostasis pathways during short duration and less extreme stressors or stressors that can be avoided by behavioral changes. Neuronal regulation of systemic proteostasis allows the nervous system to monitor environmental variables and more effectively partition finite energy resources between different organismal processes. Our studies add to a growing body of work demonstrating that intercellular communication between neuronal and non-neuronal cells plays a critical role in integrating cellular stress resistance with other organismal physiological demands and associated energy costs. mRNA expression profiling of synchronized L4 stage wild-type N2 Bristol and VC1262 osm-9(ok1677) C. elegans strains under control (51mM NaCl) and hypertonic stress (200mM NaCl).

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Disruption of STIM1-mediated Ca2+ sensing and energy metabolism in adult skeletal muscle compromises exercise tolerance, proteostasis and lean mass

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