Abstract
Aging results in the progressive accumulation of senescent cells in tissues that display loss of proliferative capacity and acquire a senescence-associated secretory phenotype (SASP). The tumor suppressor, p16 INK4A , which slows the progression of the cell cycle, is highly expressed in most senescent cells and the removal of p16-expressing cells has been shown to be beneficial to tissue health. Although much work has been done to assess the effects of cellular senescence on a variety of different organs, little is known about the effects on skeletal muscle and whether reducing cellular senescent load would provide a therapeutic benefit against age-related muscle functional decline. We hypothesized that whole-body ablation of p16-expressing cells in the advanced stages of life in mice would provide a therapeutic benefit to skeletal muscle structure and function. Treatment of transgenic p16-3MR mice with ganciclovir (GCV) from 20 to 26 months of age resulted in reduced p16 mRNA levels in muscle. At 26 months of age, the masses of tibialis anterior, extensor digitorum longus, gastrocnemius and quadriceps muscles were significantly larger in GCV-treated compared with vehicle-treated mice, but this effect was limited to male mice. Maximum isometric force for gastrocnemius muscles was also greater in GCV-treated male mice compared to controls. Further examination of muscles of GCV- and vehicle-treated mice showed fewer CD68-positive macrophages present in the tissue following GCV treatment. Plasma cytokine levels were also measured with only one, granulocyte colony stimulating factor (G-CSF), out of 22 chemokines analyzed was reduced in GCV-treated mice. These findings show that genetic ablation of p16+ senescent cells provides moderate and sex specific therapeutic benefits to muscle mass and function.
Highlights
Biological aging is characterized by the progressive accumulation of tissue damage that leads to an overall reduction in both lifespan and healthspan
Body mass did not differ between GCV+ and GCV− mice regardless of sex (Supplementary Figure 1), muscle masses are expressed in absolute terms, rather than normalized by body mass
Extensor digitorum longus (EDL), tibialis anterior (TA), gastrocnemius (GTN), and quadriceps (Quads) muscle masses were 12%, 19%, 11%, and 16% greater, respectively, in male GCV+ mice compared to vehicle controls (Figure 2), whereas plantaris and soleus muscle masses were not different between GCV+ and GCV− mice
Summary
Biological aging is characterized by the progressive accumulation of tissue damage that leads to an overall reduction in both lifespan and healthspan. Unlike congenital diseases that can be attributed to a single gene mutation, the dysfunction and pathologies that accompany aging are a result of abnormalities in many cellular and molecular processes. These include genomic instability, telomere attrition, mitochondrial dysfunction, stem cell exhaustion, loss of proteostasis, and cellular senescence (López-Otín et al, 2013). There are several broad clinical and physiological presentations that are associated with frailty These hallmarks consist of a progressive decline in muscle mass and resultant decrease in strength, termed sarcopenia (Bortz, 2002; Studenski and Pahor, 2009). There is a critical need to elucidate the mechanisms responsible for age-related muscle atrophy and weakness to develop more effective and broadly applicable treatments for increasing healthspan
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