Muscle-Specific Cellular and Molecular Adaptations to Late-Life Voluntary Concurrent Exercise

Abstract

Murine exercise models can provide information on factors that influence muscle adaptability with aging, but few translatable solutions exist. Progressive weighted wheel running (PoWeR) is a simple, voluntary, low-cost, high-volume endurance/resistance exercise approach for training young mice. In the current investigation, aged mice (22-month-old) underwent a modified version of PoWeR for 8 weeks. Muscle functional, cellular, biochemical, transcriptional, and myonuclear DNA methylation analyses provide an encompassing picture of how muscle from aged mice responds to high-volume combined training. Mice run 6-8 km/day, and relative to sedentary mice, PoWeR increases plantarflexor muscle strength. The oxidative soleus of aged mice responds to PoWeR similarly to young mice in every parameter measured in previous work; this includes muscle mass, glycolytic-to-oxidative fiber type transitioning, fiber size, satellite cell frequency, and myonuclear number. The oxidative/glycolytic plantaris adapts according to fiber type, but with modest overall changes in muscle mass. Capillarity increases markedly with PoWeR in both muscles, which may be permissive for adaptability in advanced age. Comparison to published PoWeR RNA-sequencing data in young mice identified conserved regulators of adaptability across age and muscles; this includes Aldh1l1 which associates with muscle vasculature. Agrn and Samd1 gene expression is upregulated after PoWeR simultaneous with a hypomethylated promoter CpG in myonuclear DNA, which could have implications for innervation and capillarization. A promoter CpG in Rbm10 is hypomethylated by late-life exercise in myonuclei, consistent with findings in muscle tissue. PoWeR and the data herein are a resource for uncovering cellular and molecular regulators of muscle adaptation with aging.

Multi-transcriptome analysis following an acute skeletal muscle growth stimulus yields tools for discerning global and MYC regulatory networks

“…p=0.013) (Figure 4E), similar to what occurred in myonuclei during overload (Table S10). Type 2a myosin is associated with oxidative metabolism in murine muscle (79,80). Lower Myh2 may be part of a Warburg-like program that accompanies rapid muscle growth (38,39).…”

“…Library preparation for Experiment 4 was low-input and utilized the SMARTer pico kit (TaKaRa, Shiga, Japan), as described by the National Genomics Infrastructure at SciLifeLab (Stockholm, Sweden). RNA for Experiments 1, 2, 3, and 5 were sequenced by Novogene on an Illumina HiSeq using 150 bp paired-end sequencing, as we have done previously (80,104). Experiment 4 was sequenced by the SciLifeLab on a NovaSeq 6000 (150 bp paired-end).…”

Ablation of SAMD1 in Mice Causes Failure of Embryonic Blood Vessel Maturation and Embryonic Lethality

“…Upon mouse ES cell differentiation, the absence of SAMD1 enhances the expression of genes involved in neuronal pathways, while factors important for metabolism and angiogenesis are downregulated (Supplementary Figure S3) 4 . In addition to gene regulatory functions SAMD1 may also have a role in atherosclerosis 1,3 and muscle adaptation 15 .…”

“…Further work demonstrated that SAMD1 deletion in HepG2 hepatocellular carcinoma cells leads to a global readjustment of the active H3K4me2 chromatin mark and a more favorable gene signature, supporting an oncogenic role in this context 12 . SAMD1 has also been described to play a role in antiphospholipid syndrome 14 and muscle adaptation 15 , implying a rather versatile biological function. Taken together, these ndings suggest that SAMD1 likely has a function in multiple biological processes and diseases, but the biological role of SAMD1 at an organismal level has yet to be investigated.…”

Aerobic exercise training resets the human skeletal muscle methylome 10 years after breast cancer treatment and survival

“…In contrast, both acute exercise and chronic training have been shown to decrease methylation (i.e., hypomethylation) in both human and mouse skeletal muscle 17,18,35–37 . Therefore, exercise and increased physical activity are proposed to be epigenetically anti‐aging in skeletal muscle 28,29,38–42 . However, the role of exercise training on the ability to restore the epigenetic landscape and reduce the acceleration of epigenetic aging in skeletal muscle after cancer survival is currently unknown.…”