Female aging: when translational models don't translate.

For many pathologies associated with aging, female patients present with higher morbidity and more frequent adverse events from treatments compared to male patients. While preclinical models are the foundation of our mechanistic understanding of age-related diseases, the most common models fail to recapitulate archetypical female aging trajectories. For example, while over 70% of the top age-related diseases are influenced by the systemic effects of reproductive senescence, we found that preclinical studies that include menopausal phenotypes modeling those seen in humans make up <1% of published aging biology research.

Extracellular vesicle distribution and localization in skeletal muscle at rest and following disuse atrophy.

Background: Skeletal muscle (SkM) is a large, secretory organ that produces and releases myokines that can have autocrine, paracrine, and endocrine effects. Whether extracellular vesicles (EVs) also play a role in the SkM adaptive response and ability to communicate with other tissues is not well understood. The purpose of this study was to investigate EV biogenesis factors, marker expression, and localization across cell types in the skeletal muscle.

Dynamical modeling reveals RNA decay mediates the effect of matrix stiffness on aged muscle stem cell fate.

Loss of muscle stem cell (MuSC) self-renewal with aging reflects a combination of influences from the intracellular (e.g., post-transcriptional modifications) and extracellular (e.

The transcript interactome of skeletal muscle RNA binding protein motif 3 (RBM3).

Post-transcriptional regulation of gene expression represents a critical regulatory step in the production of a functional proteome. Elevated expression of post-transcriptional regulator RNA binding motif protein 3 (RBM3), an RNA binding protein in the cold-shock family, is positively correlated with skeletal muscle growth in adult mice. However, mechanisms through which RBM3 exerts its effects are largely unknown.

Bioengineered 3D Skeletal Muscle Model Reveals Complement 4b as a Cell-Autonomous Mechanism of Impaired Regeneration with Aging.

A mechanistic understanding of cell-autonomous skeletal muscle changes after injury can lead to novel interventions to improve functional recovery in an aged population. However, major knowledge gaps persist owing to limitations of traditional biological aging models. 2D cell culture represents an artificial environment, while aging mammalian models are contaminated by influences from non-muscle cells and other organs.

Mechanotherapy Reprograms Aged Muscle Stromal Cells to Remodel the Extracellular Matrix during Recovery from Disuse.

Aging is accompanied by reduced remodeling of skeletal muscle extracellular matrix (ECM), which is exacerbated during recovery following periods of disuse atrophy. Mechanotherapy has been shown to promote ECM remodeling through immunomodulation in adult muscle recovery, but not during the aged recovery from disuse. In order to determine if mechanotherapy promotes ECM remodeling in aged muscle, we performed single cell RNA sequencing (scRNA-seq) of all mononucleated cells in adult and aged rat gastrocnemius muscle recovering from disuse, with (REM) and without mechanotherapy (RE).

Extracellular vesicles released from stress-induced prematurely senescent myoblasts impair endothelial function and proliferation.

New Findings: What is the central question of this study? What is the impact of stress-induced premature senescence on skeletal muscle myoblast-derived extracellular vesicles (EVs) and myoblast-endothelial cell crosstalk? What is the main finding and its importance? Hydrogen peroxide treatment of human myoblasts induced stress-induced premature senescence (SIPS) and increased the release of exosome-sized EVs (30-150 nm in size) five-fold compared to untreated controls. Treatment of SIPS myoblast-derived EVs on endothelial cells increased senescence markers and decreased proliferation. Gene expression analysis of SIPS myoblast-derived EVs revealed a four-fold increase in senescence factor transforming growth factor-β.

Age-Related Susceptibility to Muscle Damage Following Mechanotherapy in Rats Recovering From Disuse Atrophy.

The inability to fully recover lost muscle mass following periods of disuse atrophy predisposes older adults to lost independence and poor quality of life. We have previously shown that mechanotherapy at a moderate load (4.5 N) enhances muscle mass recovery following atrophy in adult, but not older adult rats.

Skeletal muscle RBM3 expression is associated with extended lifespan in Ames Dwarf and calorie restricted mice.

RNA binding protein motif 3 (RBM3) is an RNA-binding and cold shock protein that protects myoblasts and promotes skeletal muscle hypertrophy by enhancing mRNA stability and translation. Muscle size is decreased during aging; however, it is typically delayed in models of extended lifespan such as the long-lived Ames Dwarf (df/df) mice and calorie restricted (CR) animals compared to age-matched controls. In light of the protective and anabolic effects of RBM3 in muscle, we hypothesized that RBM3 expression is higher in long-lived animal models.

Muscle from aged rats is resistant to mechanotherapy during atrophy and reloading.

Massage is a viable mechanotherapy to improve protein turnover during disuse atrophy and improve muscle regrowth during recovery from disuse atrophy in adult muscle. Therefore, we investigated whether massage can cause beneficial adaptations in skeletal muscle from aged rats during normal weight-bearing (WB) conditions, hindlimb suspension (HS), or reloading (RE) following HS. Aged (30 months) male Fischer 344/Brown Norway rats were divided into two experiments: (1) WB for 7 days (WB, n = 8), WB with massage (WBM, n = 8), HS for 7 days (HS7, n = 8), or HS with massage (HSM, n = 8), and (2) WB for 14 days (WB14, n = 8), HS for 14 days (HS14, n = 8), reloading (RE, n = 10), or reloading with massage (REM, n = 10) for 7 days following HS.

Massage as a mechanotherapy promotes skeletal muscle protein and ribosomal turnover but does not mitigate muscle atrophy during disuse in adult rats.

Aim: Interventions that decrease atrophy during disuse are desperately needed to maintain muscle mass. We recently found that massage as a mechanotherapy can improve muscle regrowth following disuse atrophy. Therefore, we aimed to determine if massage has similar anabolic effects when applied during normal weight bearing conditions (WB) or during atrophy induced by hindlimb suspension (HS) in adult rats.

RNA-binding proteins: The next step in translating skeletal muscle adaptations?

The decline of skeletal muscle mass during illness, injury, disuse, and aging is associated with poor health outcomes. Therefore, it is important to pursue a greater understanding of the mechanisms that dictate skeletal muscle adaptation. In this review, we propose that RNA-binding proteins (RBPs) comprise a critical regulatory node in the orchestration of adaptive responses in skeletal muscle.