Category: Publications (Page 3 of 19)

p38α kinase governs muscle strength through PGC1α in mice

07/10/2024 / Sabio lab

Leticia Herrera-Melle, Beatriz Cicuéndez, Juan Antonio López, Phillip A. Dumesic, Sarah E. Wilensky, Elena Rodríguez, Luis Leiva-Vega, Ainoa Caballero, Marta León, Jesús Vázquez, Bruce M. Spiegelman, Cintia Folgueira, Alfonso Mora & Guadalupe Sabio.

Aims: skeletal muscle, with its remarkable plasticity and dynamic adaptation, serves as a cornerstone of locomotion and metabolic homeostasis in the human body. Muscle tissue, with its extraordinary capacity for force generation and energy expenditure, plays a fundamental role in the movement, metabolism, and overall health. In this context, we sought to determine the role of p38α in mitochondrial metabolism since mitochondrial dynamics play a crucial role in the development of muscle-related diseases that result in muscle weakness.

Higher muscle strength in p38αMCK-KO mice (Image: Alfonso Mora).

Methods: we conducted our study using male mice (MCK-cre, p38α^MCK-KO and PGC1α ^MCK-KO) and mouse primary myoblasts. We analyzed mitochondrial metabolic, physiological parameters as well as proteomics, western blot, RNA-seq analysis from muscle samples.

Results: our findings highlight the critical involvement of muscle p38α in the regulation of mitochondrial function, a key determinant of muscle strength. The absence of p38α triggers changes in mitochondrial dynamics through the activation of PGC1α, a central regulator of mitochondrial biogenesis. These results have substantial implications for understanding the complex interplay between p38α kinase, PGC1α activation, and mitochondrial content, thereby enhancing our knowledge in the control of muscle biology.

Conclusions: this knowledge holds relevance for conditions associated with muscle weakness, where disruptions in these molecular pathways are frequently implicated in diminishing physical strength. Our research underscores the potential importance of targeting the p38α and PGC1α pathways within muscle, offering promising avenues for the advancement of innovative treatments. Such interventions hold the potential to improve the quality of life for individuals affected by muscle-related diseases.

Acta Physiol (Oxf) 2024; 3:e14234.

Remodeling p38 signaling in muscle controls locomotor activity via IL-15

20/08/2024 / Sabio lab

Cintia Folgueira, Leticia Herrera-Melle, Juan Antonio López, Victor Galvan-Alvarez, Marcos Martin-Rincon, María Isabel Cuartero, Alicia García-Culebras, Phillip A. Dumesic, Elena Rodríguez, Luis Leiva-Vega, Marta León, Begoña Porteiro, Cristina Iglesias, Jorge L. Torres, Lourdes Hernández-Cosido, Clara Bonacasa, Miguel Marcos, María Ángeles Moro, Jesús Vázquez, Jose A. L. Calbet, Bruce M. Spiegelman, Alfonso Mora & Guadalupe Sabio.

Skeletal muscle has gained recognition as an endocrine organ releasing myokines upon contraction during physical exercise. These myokines exert both local and pleiotropic health benefits, underscoring the crucial role of muscle function in countering obesity and contributing to the overall positive effects of exercise on health.

Active p38γ increases locomotor activity (Image: Cintia Folgueira).

Here, we found that exercise activates muscle p38γ, increasing locomotor activity through the secretion of interleukin-15 (IL-15). IL-15 signals in the motor cortex, stimulating locomotor activity. This activation of muscle p38γ, leading to an increase locomotor activity, plays a crucial role in reducing the risk of diabetes and liver steatosis, unveiling a vital muscle-brain communication pathway with profound clinical implications. The correlation between p38γ activation in human muscle during acute exercise and increased blood IL-15 levels highlights the potential therapeutic relevance of this pathway in treating obesity and metabolic diseases.

These findings provide valuable insights into the molecular basis of exercise-induced myokine responses promoting physical activity.

Sci Adv 2024; 10 (33): eadn5993.

Estrogens prevent the hypothalamus-periphery crosstalk induced by olanzapine intraperitoneal treatment in female mice: effects on brown/beige adipose tissues and liver

16/05/2024 / Sabio lab

Vítor Ferreira, Cintia Folgueira, Ángela Montes-San Lorenzo, Andrea Rodríguez-López, Eva Gonzalez-Iglesias, Pablo Zubiaur, Francisco Abad-Santos, Guadalupe Sabio, Patricia Rada & Ángela M Valverde.

Olanzapine (OLA) is a highly obesogenic second-generation antipsychotic (SGA). Recently we demonstrated that, contrarily to OLA oral treatment, intraperitoneal (i.p.) administration resulted in weight loss and absence of hepatic steatosis in wild-type (WT) and protein tyrosine phosphatase 1B (PTP1B)-deficient (KO) male mice. This protection relied on two central-peripheral axes connecting hypothalamic AMPK with brown/inguinal white adipose tissue (BAT/iWAT) uncoupling protein-1 (UCP-1) and hypothalamic JNK with hepatic fatty acid synthase (FAS).

Olanzapine reduces body weight exclusively in ovariectomized mice (Image: Cintia Folgueira).

Herein, we addressed OLA i.p. treatment effects in WT and PTP1B-KO female mice. Contrarily to our previous results in WT females receiving OLA orally, the i.p. treatment did not induce weight gain or hyperphagia. Molecularly, in females OLA failed to diminish hypothalamic phospho-AMPK or elevate BAT UCP-1 and energy expenditure (EE) despite the preservation of iWAT browning. Conversely, OLA i.p. treatment in ovariectomized mice reduced hypothalamic phospho-AMPK, increased BAT/iWAT UCP-1 and EE, and induced weight loss as occurred in males. Pretreatment of hypothalamic neurons with 17β-estradiol (E₂) abolished OLA effects on AMPK. Moreover, neither hypothalamic JNK activation nor hepatic FAS upregulation were found in WT and PTP1B-KO females receiving OLA via i.p. Importantly, this axis was reestablished upon ovariectomy. In this line, E₂ prevented OLA-induced phospho-JNK in hypothalamic neurons.

These results support the role of estrogens in sex-related dimorphism in OLA treatment. This study evidenced the benefit of OLA i.p. administration in preventing its obesogenic effects in female mice that could offer clinical value.

BBA Mol Basis Dis 2024; 1870 (5): 167227.