Metabolomic Analysis of Skeletal Muscle in Aged Mice

Abstract

Sarcopenia is the age-induced, progressive loss of skeletal muscle mass and function. To better understand changes in skeletal muscle during sarcopenia, we performed a metabolomic analysis of skeletal muscle in young (8-week-old) and aged (28-month-old) mice by using capillary electrophoresis with electrospray ionization time-of-flight mass spectrometry. Principal component analysis showed clear changes in metabolites between young and aged mice. Glucose metabolism products were decreased in aged mice, specifically fructose 1,6-diphosphate (0.4-fold) and dihydroxyacetone phosphate (0.6-fold), possibly from decreased glycolytic muscle fibers. Multiple metabolic products associated with phospholipid metabolism were significantly changed in aged mice, which may reflect changes in cell membrane phospholipids of skeletal muscle. Products of polyamine metabolism, which are known to increase nucleic acid and protein synthesis, decreased in spermine (0.5-fold) and spermidine (0.6-fold) levels. By contrast, neurotransmitter levels were increased in skeletal muscle of aged mice, including acetylcholine (1.8-fold), histamine (2.6-fold), and serotonin (1.7-fold). The increase in acetylcholine might compensate for age-associated dropout of neuromuscular junctions, whereas the increases in histamine and serotonin might be due to muscle injury associated with aging. Further analysis focusing on the altered metabolites observed in this study will provide essential data for understanding aging muscles.

Older adults with sarcopenia have distinct skeletal muscle phosphodiester, phosphocreatine, and phospholipid profiles

“…Aging has been shown to increase skeletal muscle phospholipids, as Schunk et al have shown, using 31 P‐MRS, phosphomonoester content, an in vivo readout of PC and PE is elevated in muscle of older adults (Schunk et al, 1999). Additionally, recent evidence by Uchitomi and colleagues has shown differential phospholipid composition in aged rodent muscle, with the majority of phospholipids increased in aged skeletal muscle in comparison to younger counterparts (Uchitomi et al, 2019). The changes in phospholipid composition were associated with reduced type IIb myofiber size in aged muscle (Uchitomi et al, 2019), which is similar to our findings revealing a negative association between phospholipids (PC, PE, and PG) with muscle volume.…”

“…Additionally, recent evidence by Uchitomi and colleagues has shown differential phospholipid composition in aged rodent muscle, with the majority of phospholipids increased in aged skeletal muscle in comparison to younger counterparts (Uchitomi et al, 2019). The changes in phospholipid composition were associated with reduced type IIb myofiber size in aged muscle (Uchitomi et al, 2019), which is similar to our findings revealing a negative association between phospholipids (PC, PE, and PG) with muscle volume. While in contrast to recent reports that showed reducing PE levels in skeletal muscle by inhibiting key phospholipid synthesis pathways (phosphatidylserine decarboxylase) results in muscle atrophy (Heden et al, 2019; Selathurai et al, 2019), our findings and those by Uchitomi et al (2019) reveal that age‐induced muscle atrophy may be linked to elevated phospholipids levels in skeletal muscle.…”

Distinct Roles of Zmynd17 and PGC1α in Mitochondrial Quality Control and Biogenesis in Skeletal Muscle

“…These structures are also found in muscle of aged mice (Lin et al, 2018), suggesting that Zmynd17deletion accelerates muscle senescence. It has been reported that type IIb fibers, but not IIx or IIa fibers, are markedly affected by aging, which is related to muscle atrophy, known as sarcopenia (Holloszy et al, 1991;Uchitomi et al, 2019). Presumably, type FIGURE 4 | Voluntary exercise attenuates mitochondrial abnormalities of Zmynd17-KO;PGC1α-transgenic mice.…”

The biphasic and age-dependent impact of Klotho on hallmarks of aging and skeletal muscle function

“…In humans, sarcopenic declines in skeletal muscle mass typically manifest in the fourth decade of life (51,52). The onset of sarcopenia in mice, on the other hand, has not been welldocumented (53,54), and studies of sarcopenia in animal models often exclude the oldest-old cohort (53,55,56). We found that decreased muscle mass and functiontwo of the classical markers of sarcopeniabecome prominent in the oldest-old group for both male and female mice, whereas muscle declines in old mice are relatively modest.…”