Skeletal muscle aging, cellular senescence, and senotherapeutics: Current knowledge and future directions

Abstract

Cellular senescence is a state of cell cycle arrest induced by several forms of metabolic stress. Senescent cells accumulate with advancing age and have a distinctive phenotype, characterized by profound chromatin alterations and a robust senescence-associated secretory phenotype (SASP) that exerts negative effects on tissue health, both locally and systemically. In preclinical models, pharmacological agents that eliminate senescent cells (senotherapeutics) restore health and youthful properties in multiple tissues. To date, however, very little is understood about the vulnerability of terminally-differentiated skeletal muscle fibers and the resident mononuclear cells that populate the interstitial microenvironment of skeletal muscle to senescence, and their contribution to the onset and progression of skeletal muscle loss and dysfunction with aging. Scientific advances in these areas have the potential to highlight new therapeutic approaches to optimize late-life muscle health. To this end, this review highlights the current evidence and the key questions that need to be addressed to advance the field's understanding of cellular senescence as a mediator of skeletal muscle aging and the potential for emerging senescent cell-targeting therapies to counter age-related deficits in muscle mass, strength, and function. This article is part of the Special Issue - Senolytics - Edited by Joao Passos and Diana Jurk.

Keywords: Fibroadipogenic progenitor cells; Muscle fiber; Sarcopenia; Satellite cells; Senescence-associated secretory phenotype; Senolytics.

Figure 1.. The cellular composition of skeletal muscle.

Skeletal muscle tissue is comprised of several cell types and nuclear populations, including muscle fibers and their resident myonuclei, fibroadipogenic progenitors (FAPs), endothelial cells, pericytes, neurons, macrophages, satellite cells, tenocytes, and neutrophils. The estimated percentages reported reflect the relative proportion of nuclei present in bulk skeletal muscle samples. These estimates are based on data from single cell and single nucleus RNA-sequencing experiments of mouse skeletal muscle. Created with BioRender.com

Figure 2.. Evidence for cellular senescence in skeletal muscle.

Though heterogenous, senescent cells exhibit several core properties, which can be used in for their identification. These include but are not limited to senescence inducers (e.g., DNA damage, telomere associated foci), cyclin dependent kinase inhibitors (e.g., p16^INK4a and p21), SASP components (e.g., cytokines, chemokines, matrix remodeling proteins, and growth factors), and distinct cellular markers (e.g., SA-βgal, distension of satellite DNA sequences, karyomegaly). The level of evidence in the published literature for core properties of the senescence program is categorized as none, limited, moderate, or strong for bulk skeletal muscle tissue (includes muscle fibers and additional cell types in the interstitial microenvironment), muscle fibers, fibroadipogenic progenitors (FAPs), endothelial cells, satellite cells, and macrophages. Created with BioRender.com