Yihao Zhou

Muscle regenerative capacity declines with aging and disease, which leads to muscle loss and reduced lifespan. Muscle regenerative failure is related to a disrupted network orchestrated by multiple muscle-harbored cell types; whether and how the interplay between macrophages and myofibers contributes to this process is largely unknown. Herein, we report upregulation of histone methyltransferase G9a in both aged human muscle and mouse muscle after injury. Deletion of G9a in either myeloid cells or myofibers accelerates muscle regeneration. Mechanistically, G9a down-regulates macrophage-derived interleukin 13 (IL13) and suppresses myofiber-derived myokine musclin, respectively, to inhibit myogenesis and macrophage phenotype transition during muscle regeneration. Either IL13 or musclin, per se, accelerated muscle regeneration, and their combined administration showed synergistic effects with therapeutic potentials for muscle degeneration disorders. Collectively, we highlight a crosstalk between macrophages and myofibers through IL13-Stat6 signaling and musclin, both regulated by G9a, which steers a pro-recovery microenvironment after muscle injury, with therapeutic potentials for muscle degeneration disorders.

Fasting-induced metabolic remodeling is a fundamental process maintaining systemic homeostasis, with profound implications for metabolic disease interventions. During fasting, liver establishes a regulatory network centered on gluconeogenesis that integrates major fuels to keep physiological energy homeostasis. Here, we report that GAPDH, a key enzyme in both glycolysis and gluconeogenesis, senses fasting stress in the liver. Compared to wildtype controls, hepatocyte Gapdh deficiency (Gap^Alb) mice show comparable blood glucose, decreased amino acid levels and aggravated lipid accumulation in the liver after overnight fasting. Mechanistically, Gapdh depletion decreases serine levels, and serine supplementation inhibits PA-DAG (phosphatidic acid-diacylglycerols) axis by downregulating Lipin1 (a phosphohydrolase in DAG synthesis) upon overnight fasting. Furthermore, knockdown of Lipin1 rescued the effects observed in fasted Gap^Alb mice. Similarly, Gap^Alb mice showed enhanced hepatic lipid accumulation under ketogenic diets, and serine supplementation abolished these effects. Together, we find hepatic GAPDH as a central hub in glucose-amino acid-fat metabolism during nutritional limitation.

Acute kidney injury (AKI) has high incidence and mortality rates. Present treatments are mostly symptomatic and cause side effects due to systemic distribution; thus, targeted kidney drug delivery is desired. Transmembrane kidney injury molecule-1 (KIM1) is expressed at low levels in normal kidneys but markedly up-regulated following injury, making it an ideal marker/target for injured kidneys. Here, assisted by AlphaFold, we constructed a library of 1885 peptides that target the extracellular Ig V domain of KIM1 based on interacting fragments from 47 potential KIM1 binding proteins followed by systemic optimization according to their binding energies with KIM1. Experimental validation of top candidates (TKP 1-5) demonstrated that TKP 4 efficiently targeted injured renal cells/kidneys, with its specificity demonstrated in KIM1 knockout cells/mice. TKP 4–decorating liposomes were loaded with nystatin, a renal-protective compound with systemic side effects, and efficiently targeted injured mouse kidneys and alleviated AKI. This work establishes a virtual platform to screen/identify drug delivery candidates with broad research/therapeutic potentials.