Abstract
Mammalian skeletal muscle contains heterogenous myofibers with different contractile and metabolic properties that sustain muscle mass and endurance capacity. The transcriptional regulators that govern these myofiber gene programs have been elucidated. However, the hormonal cues that direct the specification of myofiber types and muscle endurance remain largely unknown. Here, we uncover the secreted factor Tsukushi (TSK) as an extracellular signal that is required for maintaining muscle mass, strength, and endurance capacity and that contributes to muscle regeneration. Mice lacking TSK exhibited reduced grip strength and impaired exercise capacity. Muscle transcriptomic analysis revealed that TSK deficiency results in a remarkably selective impairment in the expression of myofibrillar genes, characteristic of slow-twitch muscle fibers, that is associated with abnormal neuromuscular junction formation. AAV-mediated overexpression of TSK failed to rescue these myofiber defects in adult mice, suggesting that the effects of TSK on myofibers are likely restricted to certain developmental stages. Finally, mice lacking TSK exhibited diminished muscle regeneration following cardiotoxin-induced muscle injury. These findings support a crucial role of TSK as a hormonal cue in the regulation of contractile gene expression, endurance capacity, and muscle regeneration.
Highlights
Skeletal myofibers in mammals exhibit remarkable heterogeneity and plasticity [1,2,3]
TSK is required for maintaining skeletal muscle mass and endurance capacity In previous studies, we demonstrated that mice deficient in TSK exhibited remarkable resistance to high-fat diet (HFD)-induced obesity and its associated metabolic disorders, including insulin resistance, adipose dysfunction, and hepatic steatosis [18,19,20]
Knockout (KO) mice were slightly smaller than wild type (WT) littermates when fed chow diet and gained significantly less weight following HFD feeding (Figure S1A-B)
Summary
Skeletal myofibers in mammals exhibit remarkable heterogeneity and plasticity [1,2,3]. Based on the expression of myosin heavy chain (MYH) isoforms and their metabolic properties, skeletal muscle fibers can be classified as slow-twitch, type I and fast-twitch, type II (IIa, IIb and IIx) fibers. Type I and IIa myofibers have relatively high mitochondrial content and oxidative capacity whereas type IIb and IIx myofibers rely primarily on glycolytic metabolism for energy production. The slow-twitch myofibers are typically more fatigue-resistant and play a crucial role in sustaining the endurance capacity of skeletal muscle. The extracellular signals and hormonal cues that specify the metabolic and contractile properties of skeletal myofibers remain poorly defined
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