Abstract
ObjectiveLeptin receptors are abundant in human skeletal muscle, but the role of leptin in muscle growth, development and aging is not well understood. Here we utilized a novel mouse model lacking all functional leptin receptor isoforms (POUND mouse, Leprdb/lb) to determine the role of leptin in skeletal muscle.Methods and FindingsSkeletal muscle mass and fiber diameters were examined in POUND mice, and primary myoblast cultures were used to determine the effects of altered leptin signaling on myoblast proliferation and differentiation. ELISA assays, integrated pathway analysis of mRNA microarrays, and reverse phase protein analysis were performed to identify signaling pathways impacted by leptin receptor deficiency. Results show that skeletal muscle mass and fiber diameter are reduced 30–40% in POUND mice relative to wild-type controls. Primary myoblast cultures demonstrate decreased proliferation and decreased expression of both MyoD and myogenin in POUND mice compared to normal mice. Leptin treatment increased proliferation in primary myoblasts from muscles of both adult (12 months) and aged (24 months) wild-type mice, and leptin increased expression of MyoD and myogenin in aged primary myoblasts. ELISA assays and protein arrays revealed altered expression of molecules associated with the IGF-1/Akt and MAPK/MEK signaling pathways in muscle from the hindlimbs of mice lacking functional leptin receptors.ConclusionThese data support the hypothesis that the adipokine leptin is a key factor important for the regulation of skeletal muscle mass, and that leptin can act directly on its receptors in peripheral tissues to regulate cell proliferation and differentiation.
Highlights
The cytokine-like hormone leptin is an important factor linking food intake with energy expenditure and body composition [1,2]
Leptin is secreted from fat cells, but skeletal muscle is a source of leptin [3], and serum leptin levels increase with increased muscle mass [4]
Myostatin ELISA kits were purchased from Alpco diagnostic and performed according to manufacturer’s protocol as we have described previously (33)
Summary
The cytokine-like hormone leptin is an important factor linking food intake with energy expenditure and body composition [1,2]. Leptin-deficiency increases expression of the muscle-wasting protein myostatin in myocytes [8], and the functional characteristics of skeletal muscle in leptin-deficient ob/ob mice have been noted to resemble those of aged rodents [9]. Serum leptin and muscle mass were found to decrease with age in C57BL6 mice [10], but leptin treatment increased muscle mass and muscle fiber size in aged mice [11]. Consistent with an anabolic role for leptin in the maintenance of skeletal muscle leptin treatment increases muscle mass in leptin-deficient ob/ob mice [14,15] and decreases the expression of catabolic factors such as the ubiquitin ligases muscle RING-finger protein-1 (MuRF1) and atrogin-1 (MAFbx) [16]
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