Comparative proteomic profiling reveals a role for Cisd2 in skeletal muscle aging

Abstract

SummarySkeletal muscle has emerged as one of the most important tissues involved in regulating systemic metabolism. The gastrocnemius is a powerful skeletal muscle composed of predominantly glycolytic fast‐twitch fibers that are preferentially lost among old age. This decrease in gastrocnemius muscle mass is remarkable during aging; however, the underlying molecular mechanism is not fully understood. Strikingly, there is a ~70% decrease in Cisd2 protein, a key regulator of lifespan in mice and the disease gene for Wolfram syndrome 2 in humans, within the gastrocnemius after middle age among mice. A proteomics approach was used to investigate the gastrocnemius of naturally aged mice, and this was compared to the autonomous effect of Cisd2 on gastrocnemius aging using muscle‐specific Cisd2 knockout (mKO) mice as a premature aging model. Intriguingly, dysregulation of calcium signaling and activation of UPR/ER stress stand out as the top two pathways. Additionally, the activity of Serca1 was significantly impaired and this impairment is mainly attributable to irreversibly oxidative modifications of Serca. Our results reveal that the overall characteristics of the gastrocnemius are very similar when naturally aged mice and the Cisd2 mKO mice are compared in terms of pathological alterations, ultrastructural abnormalities, and proteomics profiling. This suggests that Cisd2 mKO mouse is a unique model for understanding the aging mechanism of skeletal muscle. Furthermore, this work substantiates the hypothesis that Cisd2 is crucial to the gastrocnemius muscle and suggests that Cisd2 is a potential therapeutic target for muscle aging.

GAS1Deficient Enhances UPR Activity inSaccharomyces cerevisiae

“…Similar to our observations, the Caenorhabditis elegans gas-1 ( fc21 ) mutant also exhibited an upregulated mitochondrial UPR and a decreased lifespan due to an abnormal mitochondrial function [26]. In addition, muscle-specific Cisd2-knockout mice used as premature ageing models also exhibited selectively or strongly activated ER stress UPR pathways [27]. In our study, we extended these findings by demonstrating that the short-lived GAS1 -deficient strain induced the activity of UPR pathway, indicating that the UPR activity is equally induced in both short- and long-lived mutants and may be therefore uncoupled from their longevity.…”

Muscle atrophy‐related myotube‐derived exosomal microRNA in neuronal dysfunction: Targeting both coding and long noncoding RNAs

“…For natural aging, 26‐month‐old wild‐type mice with 10%–20% gray hair indicating depigmentation of the cloth were used. For premature aging, we used 3‐month‐old CDGSH iron–sulfur domain‐containing protein 2 (CISD2) muscle‐specific knockout (mKO) mice with early depigmentation and gray hair (Huang et al, ). CISD2 is a mitochondrial outer membrane protein (MOMP) that participates in maintaining mitochondrial integrity, and its deficiency drives premature aging (Chen, Kao, Chen, et al, ; Chen, Kao, Kirby, & Tsai, ).…”

“…Conversely, persistent expression of CISD2 extends life span and delays aging in the mouse model (Wu et al, ). Moreover, our recent report showed that CISD2 mKO mice shared similar proteomic profiling as naturally aged mice (Huang et al, ). These data together make CISD2 mKO mice an ideal premature aging model.…”

“…Given the role of CISD2 (Huang et al, ) and miR‐29b‐3p (Li, Chan, et al, ) in muscle atrophy and upregulation of plasma miR‐29b‐3p in CISD2 mKO mice (Figure e), we hypothesize that CISD2 may directly or indirectly upregulate miR‐29b‐3p in atrophied C2C12 myotubes. To study this, we first generated a CISD2 KO C2C12 cell line using CRISPR/Cas9n system (Figure a‐c).…”

Cisd2 haploinsufficiency: A driving force for hepatocellular carcinoma

“…Cisd2 protein is localized in the ER, the mitochondrial outer membrane and the mitochondria-associated ER membrane. Several studies have indicated that Cisd2 regulates intracellular Ca 2+ homeostasis and the redox status of various types of cell 3 , 4 . Intriguingly, our recent study has revealed that Cisd2 , which is located within the most frequently deleted region of chromosome 4q in HCC patients, is a novel haploinsufficient tumor suppressor gene 5 .…”