The adipokine leptin increases skeletal muscle mass and significantly alters skeletal muscle miRNA expression profile in aged mice

Abstract

Age-associated loss of muscle mass, or sarcopenia, contributes directly to frailty and an increased risk of falls and fractures among the elderly. Aged mice and elderly adults both show decreased muscle mass as well as relatively low levels of the fat-derived hormone leptin. Here we demonstrate that loss of muscle mass and myofiber size with aging in mice is associated with significant changes in the expression of specific miRNAs. 57 miRNAs were altered with aging in the mice and many of these miRNAs are, for the first time, reported to be associated specifically with age-related muscle atrophy. These include miR-221, previously identified in studies of myogenesis and muscle development as playing a role in the proliferation and terminal differentiation of myogenic precursors. We also treated aged mice with recombinant leptin, to determine whether leptin therapy could improve muscle mass and alter the miRNA expression profile of aging skeletal muscle. Leptin treatment significantly increased hindlimb muscle mass and extensor digitorum longus fiber size in aged mice. Furthermore, the expression of 37 miRNAs was altered in muscles of leptin treated mice. In particular, leptin treatment increased the expression of miR-31 and miR-223, miRNAs known to be elevated during muscle regeneration and repair. These findings suggest that aging in skeletal muscle is associated with marked changes in the expression of specific miRNAs, and that nutrient-related hormones such as leptin may be able to reverse muscle atrophy and alter the expression of atrophy-related miRNAs in aging skeletal muscle.

MicroRNAs and their roles in aging

“…A total of 57 miRNAs were differentially expressed in aging murine muscle tissue, including miR-221, which has been shown to regulate differentiation of myogenic precursors (Hamrick et al, 2010). Levels of miR-7, miR-468, miR-542 and miR-698 were increased the most substantially, whereas miR-124a, miR-181a, miR-221, miR-382, miR-434 and miR-455 levels were most decreased upon muscle aging (Fig.…”

“…Aging of skeletal muscle has also been associated with changes in miRNA expression levels (Hamrick et al, 2010). A total of 57 miRNAs were differentially expressed in aging murine muscle tissue, including miR-221, which has been shown to regulate differentiation of myogenic precursors (Hamrick et al, 2010).…”

“…Levels of miR-7, miR-468, miR-542 and miR-698 were increased the most substantially, whereas miR-124a, miR-181a, miR-221, miR-382, miR-434 and miR-455 levels were most decreased upon muscle aging (Fig. 3) (Hamrick et al, 2010). When miRNA expression in younger human skeletal muscle was compared with that in older muscle, 18 miRNAs were found to be differentially expressed, with let-7b and let-7e upregulated (Drummond et al, 2010).…”

Bone muscle crosstalk targets muscle regeneration pathway regulated by core circadian transcriptional repressors DEC1 and DEC2

“…Hamrick et al 73 showed that aged mice (24 months), but not 12-month-old mice, responded to injection with recombinant leptin by increasing the size and mass of muscles (including EDL), and induction in muscle of several miRNAs known to be associated with regeneration and repair. While it is tempting to presume that increased muscle in Dmp1-Cre Mbtps1 cKO mice is solely the result of paracrine signaling by leptin (Figure 6), our phenotype is not superimposable since it is evident at 12 months as well as 26 months of age (unpublished result, JP Gorski) and is restricted to SOL (not EDL) muscles.…”

Sarcopenia, Sarcopenic Obesity and Insulin Resistance

“…Muscle and fat are both metabolically active, the latter producing TNF-a, IL-6 and adipokines all of which have a direct catabolic effect on the former, and promote insulin resistance. Leptin and low adiponectin concentrations have been found to negatively impact muscle mass and lead to a decline in muscle quality (Hamrick et al 2010). On a biological level, macrophages in adipocytes or in adipose tissue, produce such proinflammatory cytokines (Fantuzzi 2005) which can upregulate the inflammatory response.…”