Dataset Information

Skeletal Muscle Proteomics of High Functioning Octogenarians

ABSTRACT: Skeletal muscle mass and function decline more precipitously after the age 75 y. To provide insights into biologically relevant mechanisms for preserving muscle mass and physical function in advanced age, a battery of physical function tests, muscle cross-sectional area by MRI and a vastus lateralis muscle biopsy were performed in 15 octogenarian world class track and field masters athletes (MA) and 14 non-athlete age- and sex-matched controls (NA). Muscle samples were analyzed using liquid-chromatography mass spectrometry to generate proteomics data, by histochemistry to identify respiratory compromised muscle fibers, and by quantitative real-time polymerase chain reaction to estimate mtDNA copy number. Physical function and muscle cross-sectional area were higher in MA than NA. Of nearly 6,000 proteins identified and quantified in muscle biopsy specimens, ~800 were differentially represented in MA versus NA. Most of the differentially represented proteins related to mitochondrial structure and function and were overrepresented in muscle of MA versus controls, including TCA cycle, respiratory electron transport capacity (ETC), cristae formation, sirtuins, and 8 mtDNA-encoded proteins. On the contrary, proteins from the spliceosome complex and nuclear pore were downregulated in MA. Consistent with proteomics, MA had fewer respiratory compromised fibers, higher mtDNA copy number, and an increased protein ratio of the cristae-bound ETC subunits relative to the outer mitochondrial membrane protein voltage dependent anion channel. In conclusion, high physical function in advanced age is associated with preservation of mitochondrial health and function, with underrepresentation of proteins that process pre-RNA and determine splicing variants, and underrepresentation of nuclear pore proteins.

INSTRUMENT(S): Q Exactive HF

ORGANISM(S): Homo Sapiens (ncbitaxon:9606)

SUBMITTER: Luigi Ferrucci Russell T. Hepple

PROVIDER: MSV000086195 | MassIVE |

SECONDARY ACCESSION(S): PXD021652

REPOSITORIES: MassIVE

ACCESS DATA

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Publications

Unbiased proteomics, histochemistry, and mitochondrial DNA copy number reveal better mitochondrial health in muscle of high-functioning octogenarians.

Ubaida-Mohien Ceereena C Spendiff Sally S Lyashkov Alexey A Moaddel Ruin R MacMillan Norah J NJ Filion Marie-Eve ME Morais Jose A JA Taivassalo Tanja T Ferrucci Luigi L Hepple Russell T RT

eLife 20220411

<h4>Background</h4>Master athletes (MAs) prove that preserving a high level of physical function up to very late in life is possible, but the mechanisms responsible for their high function remain unclear.<h4>Methods</h4>We performed muscle biopsies in 15 octogenarian world-class track and field MAs and 14 non-athlete age/sex-matched controls (NA) to provide insights into mechanisms for preserving function in advanced age. Muscle samples were assessed for respiratory compromised fibers, mitochond ...[more]

PMID: 35404238

Similar Datasets

Project description:Mitochondrial dysfunction caused by mitochondrial (mtDNA) deletions have been associated with skeletal muscle atrophy and myofiber loss. However, whether such defects occurring in myofibers cause sarcopenia is unclear. Also, the contribution of mtDNA alterations in muscle stem cells (MuSCs) to sarcopenia remain to be investigated. We expressed a dominant-negative variant of the mitochondrial helicase, which induces mtDNA alterations, specifically in differentiated myofibers (K320Eskm mice) and MuSCs (K320Emsc mice), respectively, and investigated their impact on muscle structure and function by immunohistochemistry, analysis of mtDNA and respiratory chain content, muscle transcriptome and functional tests. K320Eskm mice at 24 months of age had higher levels of mtDNA deletions compared to controls in soleus (SOL, 0.07673 % vs 0.00015 %, p=0.0167), extensor digitorium longi (EDL, 0.0649 vs 0.000925, p= 0.0015) and gastrocnemius (GAS, 0.09353 vs 0.000425, p=0.0004). K320Eskm mice revealed a progressive increase in the proportion of cytochrome c oxidase deficient fibers (COX-) in cross sections, reaching a maximum of 3.03%, 4.36%, 13.58% and 17.08% in EDL, SOL, tibialis anterior (TA) and GAS, respectively. However, mice did not show accelerated loss of muscle mass, muscle strength or physical performance. Histological analyses revealed ragged red fibers but also stimulated regeneration, indicating activation of MuSCs. RNAseq demonstrated enhanced expression of genes associated with protein synthesis, but also degradation, as well as muscle fiber differentiation and cell proliferation. In contrast, 7 days after destruction by cardiotoxin, regenerating TA of K320Emsc mice showed 30% of COX- fibers. Notably, regenerated muscle showed dystrophic changes, increased fibrosis (2.5% vs 1.6%, p=0.0003), increased abundance of fat cells (2.76% vs 0.23%, p=0.0144) and reduced muscle mass (regenerated TA: 40.0mg vs 60.2mg, p=0.0171). In contrast to muscles from K320Eskm mice, freshly isolated MuSCs from aged K320Emsc mice were completely devoid of mtDNA alterations. However, after passaging, mtDNA copy number as well as respiratory chain subunits and p62 levels gradually decreased.Taken together, accumulation of large-scale mtDNA alterations in myofibers alone is not sufficient to cause sarcopenia. Expression of K320E is tolerated in quiescent MuSCs, but progressively leads to mtDNA and respiratory chain depletion upon activation, in vivo and in vitro, possibly caused by an increased mitochondrial removal. Altogether, our results suggest that the accumulation of mtDNA alterations in myofibers activates regeneration during aging, which leads to sarcopenia if such alterations have expanded in MuSCs as well.