Molecular and phenotypic analysis of rodent models reveals conserved and species-specific modulators of human sarcopenia

Abstract

Sarcopenia, the age-related loss of skeletal muscle mass and function, affects 5–13% of individuals aged over 60 years. While rodents are widely-used model organisms, which aspects of sarcopenia are recapitulated in different animal models is unknown. Here we generated a time series of phenotypic measurements and RNA sequencing data in mouse gastrocnemius muscle and analyzed them alongside analogous data from rats and humans. We found that rodents recapitulate mitochondrial changes observed in human sarcopenia, while inflammatory responses are conserved at pathway but not gene level. Perturbations in the extracellular matrix are shared by rats, while mice recapitulate changes in RNA processing and autophagy. We inferred transcription regulators of early and late transcriptome changes, which could be targeted therapeutically. Our study demonstrates that phenotypic measurements, such as muscle mass, are better indicators of muscle health than chronological age and should be considered when analyzing aging-related molecular data.

Common Muscle Metabolic Signatures Highlight Arginine and Lysine Metabolism as Potential Therapeutic Targets to Combat Unhealthy Aging

“…We chose two months of age to replicate a prior study [ 20 ] and to capture a metabolic snapshot at the beginning of adulthood, when rapid postnatal muscle growth begins to stabilize [ 21 , 22 ]. We chose 21-months as the beginning of old age, when loss of muscle mass and function begins due to age-associated sarcopenia [ 20 , 23 ]. We collected tissues under basal metabolic conditions at ZT6 (zeitgeber time 6, noon) after a 4 h fast and during the normal physiological fasting + rest phase for nocturnal mice [ 24 ].…”

Functional Aging in Male C57BL/6J Mice Across the Life-Span: A Systematic Behavioral Analysis of Motor, Emotional, and Memory Function to Define an Aging Phenotype

“…Compared to humans, we found declines in locomotor activity ( Figure 12B ), gait velocity ( Figure 12C ), and grip strength ( Figure 12D ); these declined at younger relative ages in male mice compared to humans. Age-related changes in grip strength assessed by the four-limb wire hanging test is controversial ( DeanIII, Scozzafava et al, 1981 ; Graber et al, 2013 ; Shoji et al, 2016 ; Börsch et al, 2021 ), however, several studies have demonstrated that these physical traits apparently deteriorate in aged mice ( DeanIII, Scozzafava et al, 1981 ; Benice et al, 2006 ; Serradj and Jamon, 2007 ; Graber et al, 2013 ). DeanIII, Scozzafava et al (1981) showed, for example, that performance in the wire-hang test begins to decline between 23 and 31 months of age.…”

“…However, rigorous argument might be required when comparing the gait of bipedal human and sedentary mice. Together with possible contribution of body weight ( Oellrich et al, 2016 ) and muscle mass ( Börsch et al, 2021 ), further careful studies using other tests ( Hoffman and Winder, 2016 ; Takeshita et al, 2017 ) are necessary to determine that grip strength progressively decline with increasing age.…”

Different phases of aging in mouse old skeletal muscle

“…In the case of mice, those ranging from 18 to 24 months-of-age, which is comparable to humans of 56 – 69 years-of-age, fulfil the requirements of “young-old” age, whereas mice aged 26 months and older can be considered as “old-old” [ 10 ]. It is notable that 22 – 24 months of age is when morphological changes consistent with human sarcopenia [ 11 ] commence in mice and rats [ 12 , 13 ]. This is the period skeletal muscle mass and grip strength decline progressively with age, exhibiting prominent changes at 24-28 months of age, while whole–body mass and lean mass were relatively stable or only marginally declined [ 13 ].…”