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Summary: Skeletal 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. [ABSTRACT FROM AUTHOR]

Mutations in lamin A (LMNA) are responsible for a variety of human dystrophic and metabolic diseases. Here, we created a mouse model in which progerin, the lamin A mutant protein that causes Hutchinson–Gilford progeria syndrome (HGPS), can be inducibly overexpressed. Muscle‐specific overexpression of progerin was sufficient to induce muscular dystrophy and alter whole‐body energy expenditure, leading to premature death. Intriguingly, sarcolipin (Sln), an endoplasmic reticulum (ER)‐associated protein involved in heat production, is upregulated in progerin‐expressing and Lmna knockout (Lmna−/−) skeletal muscle. The depletion of Sln accelerated the early death of Lmna−/− mice. An examination at the molecular level revealed that progerin recruits Sln and Calnexin to the nuclear periphery. Furthermore, progerin‐expressing myoblasts presented enhanced store‐operated Ca2+ entry, as well as increased co‐localization of STIM1 and ORAI1. These findings suggest that progerin dysregulates calcium homeostasis through an interaction with a subset of ER‐associated proteins, resulting in thermogenic and metabolic abnormalities. [ABSTRACT FROM AUTHOR]

Spinocerebellar ataxia type 22 (SCA22) caused by KCND3 mutations is an autosomal dominant disorder. We established a mouse model carrying the Kcnd3 F227del mutation to study the molecular pathogenesis. Four findings were pinpointed. First, the heterozygous mice exhibited an early onset of defects in motor coordination and balance which mirror those of SCA22 patients. The degeneration and a minor loss of Purkinje cells, together with the concurrent presence of neuroinflammation, as well as the previous finding on electrophysiological changes, may all contribute to the development of the SCA22 ataxia phenotype in mice carrying the Kcnd3 F227del mutant protein. Second, the mutant protein is retained by the endoplasmic reticulum and Golgi, leading to activation of the unfolded protein response and a severe trafficking defect that affects its membrane destination. Intriguingly, profound damage of the Golgi is the earliest manifestation. Third, analysis of the transcriptome revealed that the Kcnd3 F227del mutation down-regulates a panel of genes involved in the functioning of synapses and neurogenesis which are tightly linked to the functioning of Purkinje cells. Finally, no ataxia phenotypes were detectable in knockout mice carrying a loss-of-function Kcnd3 mutation. Thus, Kcnd3 F227del is a dominant-negative mutation. This mouse model may serve as a preclinical model for exploring therapeutic strategies to treat patients. © 2024 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland., (© 2024 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.)

The multifactorial and multistage pathogenesis of hepatocellular carcinoma (HCC) has fascinated a wide spectrum of scientists for decades. While a number of major risk factors have been identified, their mechanistic roles in hepatocarcinogenesis still need to be elucidated. Many tumor suppressor genes (TSGs) have been identified as being involved in HCC. These TSGs can be classified into two groups depending on the situation with respect to allelic mutation/loss in the tumors: the recessive TSGs with two required mutated alleles and the haploinsufficient TSGs with one required mutated allele. Hepatitis B virus (HBV) is one of the most important risk factors associated with HCC. Although mice cannot be infected with HBV due to the narrow host range of HBV and the lack of a proper receptor, one advantage of mouse models for HBV/HCC research is the numerous and powerful genetic tools that help investigate the phenotypic effects of viral proteins and allow the dissection of the dose-dependent action of TSGs. Here, we mainly focus on the application of mouse models in relation to HBV-associated HCC and on TSGs that act either in a recessive or in a haploinsufficient manner. Discoveries obtained using mouse models will have a great impact on HCC translational medicine.