The skeletal muscle is the largest organ in the body and secretes circulating factors, including myokines, which are involved in various cellular signaling processes. Skeletal muscle is vital for metabolism and physiology and plays a crucial role in insulin-mediated glucose disposal. Myokines have autocrine, paracrine, and endocrine functions, serving as critical regulators of myogenic differentiation, fiber-type switching, and maintaining muscle mass. Myokines have profound effects on energy metabolism and inflammation, contributing to the pathophysiology of type 2 diabetes (T2D) and other metabolic diseases. Myokines have been shown to increase insulin sensitivity, thereby improving glucose disposal and regulating glucose and lipid metabolism. Many myokines have now been identified, and research on myokine signaling mechanisms and functions is rapidly emerging. This review summarizes the current state of the field regarding the role of myokines in tissue cross-talk, including their molecular mechanisms, and their potential as therapeutic targets for T2D.

Organophosphates are the most frequently and largely applied insecticide in the world due to their biodegradable nature. Gut microbes were shown to degrade organophosphates and cause intestinal dysfunction. The diabetogenic nature of organophosphates was recently reported but the underlying molecular mechanism is unclear. We aimed to understand the role of gut microbiota in organophosphate-induced hyperglycemia and to unravel the molecular mechanism behind this process. Here we demonstrate a high prevalence of diabetes among people directly exposed to organophosphates in rural India (n = 3080). Correlation and linear regression analysis reveal a strong association between plasma organophosphate residues and HbA1c but no association with acetylcholine esterase was noticed. Chronic treatment of mice with organophosphate for 180 days confirms the induction of glucose intolerance with no significant change in acetylcholine esterase. Further fecal transplantation and culture transplantation experiments confirm the involvement of gut microbiota in organophosphate-induced glucose intolerance. Intestinal metatranscriptomic and host metabolomic analyses reveal that gut microbial organophosphate degradation produces short chain fatty acids like acetic acid, which induces gluconeogenesis and thereby accounts for glucose intolerance. Plasma organophosphate residues are positively correlated with fecal esterase activity and acetate level of human diabetes. Collectively, our results implicate gluconeogenesis as the key mechanism behind organophosphate-induced hyperglycemia, mediated by the organophosphate-degrading potential of gut microbiota. This study reveals the gut microbiome-mediated diabetogenic nature of organophosphates and hence that the usage of these insecticides should be reconsidered.

Type 2 diabetes (T2D) is a heterogenous disease, and conventionally, peripheral insulin resistance (IR) was thought to precede islet β-cell dysfunction, promoting progression from prediabetes to T2D. New evidence suggests that T2D-lean individuals experience early β-cell dysfunction without significant IR. Regardless of the primary event (i.e., IR vs. β-cell dysfunction) that contributes to dysglycemia, significant early-onset oxidative damage and mitochondrial dysfunction in multiple metabolic tissues may be a driver of T2D onset and progression. Oxidative stress, defined as the generation of reactive oxygen species (ROS), is mediated by hyperglycemia alone or in combination with lipids. Physiological oxidative stress promotes inter-tissue communication, while pathological oxidative stress promotes inter-tissue mis-communication, and new evidence suggests that this is mediated via extracellular vesicles (EVs), including mitochondria containing EVs. Under metabolic-related stress conditions, EV-mediated cross-talk between β-cells and skeletal muscle likely trigger mitochondrial anomalies leading to prediabetes and T2D. This article reviews the underlying molecular mechanisms in ROS-related pathogenesis of prediabetes, including mitophagy and mitochondrial dynamics due to oxidative stress. Further, this review will describe the potential of various therapeutic avenues for attenuating oxidative damage, reversing prediabetes and preventing progression to T2D.

First, reducing sarcopolin (SLN) expression improves sarco/endoplasmic reticulum Ca²⁺ uptake and intracellular Ca²⁺ handling and prevents cardiomyopathy in mdx mice. Second, reducing SLN expression prevents diastolic dysfunction and improves cardiac contractility in mdx mice Third, reducing SLN expression activates apelin-mediated cardioprotective signaling pathways in mdx heart.

The p21-activated kinase 1 (PAK1) is required for insulin-stimulated glucose uptake in skeletal muscle cells. However, whether PAK1 regulates skeletal muscle mitochondrial function, which is a central determinant of insulin sensitivity, is unknown. Here, the effect of modulating PAK1 levels (knockdown via siRNA, overexpression via adenoviral transduction, and/or inhibition of activation via IPA3) on mitochondrial function was assessed in normal and/or insulin-resistant rat L6.GLUT4myc and human muscle (LHCN-M2) myotubes. Human type 2 diabetes (T2D) and non-diabetic (ND) skeletal muscle samples were also used for validation of the identified signaling elements. PAK1 depletion in myotubes decreased mitochondrial copy number, respiration, altered mitochondrial structure, downregulated PGC1α (a core regulator of mitochondrial biogenesis and oxidative metabolism) and PGC1α activators, p38 mitogen-activated protein kinase (p38MAPK) and activating transcription factor 2 (ATF2). PAK1 enrichment in insulin-resistant myotubes improved mitochondrial function and rescued PGC1α expression levels. Activated PAK1 was localized to the cytoplasm, and PAK1 enrichment concurrent with p38MAPK inhibition did not increase PGC1α levels. PAK1 inhibition and enrichment also modified nuclear phosphorylated-ATF2 levels. T2D human samples showed a deficit for PGC1α, and PAK1 depletion in LHCN-M2 cells led to reduced mitochondrial respiration. Overall, the results suggest that PAK1 regulates muscle mitochondrial function upstream of the p38MAPK/ATF2/PGC1α-axis pathway.

Duchenne muscular dystrophy (DMD) is an inherited muscle wasting disease. Metabolic impairments and oxidative stress are major secondary mechanisms that severely worsen muscle function in DMD. Here, we sought to determine whether germline reduction or ablation of sarcolipin (SLN), an inhibitor of sarco/endoplasmic reticulum (SR) Ca²⁺ ATPase (SERCA), improves muscle metabolism and ameliorates muscle pathology in the mdx mouse model of DMD. Glucose and insulin tolerance tests show that glucose clearance rate and insulin sensitivity were improved in the SLN haploinsufficient mdx ( mdx:sln^+/−) and SLN-deficient mdx ( mdx:sln^−/−) mice. The histopathological analysis shows that fibrosis and necrosis were significantly reduced in muscles of mdx:sln^+/− and mdx:sln^−/− mice. SR Ca²⁺ uptake, mitochondrial complex protein levels, complex activities, mitochondrial Ca²⁺ uptake and release, and mitochondrial metabolism were significantly improved, and lipid peroxidation and protein carbonylation were reduced in the muscles of mdx:sln^+/− and mdx:sln^−/− mice. These data demonstrate that reduction or ablation of SLN expression can improve muscle metabolism, reduce oxidative stress, decrease muscle pathology, and protects the mdx mice from glucose intolerance.