Microvascular Skeletal-Muscle Crosstalk in Health and Disease

Figures

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  Figure 1. Overview of skeletal-muscle structure. Muscle fibers are comprised of multiple myofibrils surrounded by a layer of extracellular matrix (ECM), the basal lamina, and are grouped together to form a muscle fasciculus that is encapsulated by the perimysium. Several fascicles surrounded by the epimysium form the muscle mass. The ECM is comprised of collagens, proteoglycans and fibronectin. Myogenic stem/satellite cells reside below the basal lamina and play a vital role in muscle regeneration. From Korthuis, 2011 [1].

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  Figure 2. Diagram of skeletal-muscle vascular structure. Blood flow is provided by primary arteries, which give rise to feed arteries that course toward the epimysium. Smaller branching feed arteries, i.e., arterioles give rise to terminal arterioles that branch into numerous capillaries that travel parallel to the muscle fiber. Blood returns to collecting venules which merge to form larger venules. The terminal arterioles and all capillaries perfused by one terminal arteriole and collected by one venule define the skeletal-muscle microvascular unit (MVU), the smallest functional unit for blood-flow regulation in, and the site of uptake of, substrates, oxygen and regulatory factors by skeletal muscle fibers. From Korthuis, 2011 [1].

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  Figure 3. Schematic representation of the role of the Notch pathway in cell-fate decisions in the somite. Myogenic and vascular endothelial cells are derived from the dermomyotome comprising bipotent mesodermal myogenic progenitor cells (MPC) that express the transcription factors pax3+/pax7+ and foxc2. The myogenic–endothelial cell fate of MPC cells is regulated by the Notch signaling pathway via control of the pax3: foxc2 genetic equilibrium. From Mayeuf-Louchart et al., 2014 [17].

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  Figure 4. Model of myogenic proliferation and alignment of satellite cells (SC) under the basal lamina of skeletal muscle fibers. In the embryo, pax3+ and pax3+/7+ myogenic progenitor cells (MPC) proliferate and form primary myofibers which serve as scaffolding for the formation of muscle fibers, which occurs following continued proliferation of MPCs and expression of myogenic regulatory factors including MyoD, Myf5 and Mrf4. Proliferation of myogenic cells also leads to establishment of the pool of quiescent SC which do not proliferate nor enter the myogenic lineage. From Lagha et al., 2008 [14].

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  Figure 5. Key features of dysglycemia-based chronic disease and the insulin resistance–prediabetes–type 2 diabetes spectrum. Insulin resistance is the driving factor leading to prediabetes, diabetes, and micro- and macro-vascular complications. From Kalra et al., Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy 2021:14 165–184. Originally published by and used with permission from Dove Medical Press Ltd. [43].

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  Figure 6. Endothelial insulin signaling and the associated consequences in health (A) and diabetes (B). In non-diabetic/healthy individuals, insulin binds to its membrane receptor to preferentially activate, via the insulin receptor substrate (IRS), the phosphatidyl inositol 3-kinase (PI3-K) pathway leading to the induction of endothelial nitric oxide synthase (eNOS), increased production of nitric oxide (NO) and vascular smooth muscle (VSMC) dilation. In diabetes, insulin-induced activation of PI3-kinase and NO production is compromised whereas induction of MAP-kinase is maintained, leading to production of endothlin-1 (ET-1), VSMC constriction and decreased myofiber perfusion and hypertension. From Love et al., 2021 [54].

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  Figure 7. Diagram of trans-endothelial transport of insulin in skeletal muscle. Insulin in capillaries perfusing skeletal muscle binds to and activates endothelial cell insulin receptors (IR) and IGF-I receptors (IGF-IR) to activate PI3 kinase and MEK signaling pathways that facilitate trans-endothelial transport of insulin from blood to muscle interstitium and, thus, its availability to bind to and stimulate insulin myocyte receptors. From Zheng and Liu, 2015 [52].

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  Figure 8. Schematic representation of the proposed interplay between exercise, insulin action and muscle microvasculature. Insulin stimulates endothelial-cell nitric oxide (NO) production which causes microvascular recruitment and expands endothelial surface area, leading to increased delivery to, and action of, insulin on muscle. Muscle contraction, via AMPK-dependent and -independent mechanisms, facilitates muscle-glucose and insulin uptake as well as NO-independent microvascular recruitment. From Zheng and Liu, 2015 [52].

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  Figure 9. Box-and-whisker plots of values for (A) the homeostasis model of insulin resistance and (B) the QUICKI model of insulin sensitivity in offspring of baboons untreated (eight males, four females) or treated with letrozole (five males, three females) or letrozole plus estradiol (five males, three females). Values of data bars with different letters different from each other at p < 0.01 (ANOVA and Tukey–Kramer multiple comparison test). From Albrecht et al., 2022 [40].

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  Figure 10. Box-and-whisker plots of (A) capillary (cap)/myofiber ratio (number of cap/number of myofibers) in fetuses (A) and offspring (B) delivered to baboon mothers untreated (n = 6 fetuses; n = 7 offspring) or treated with letrozole (n = 4 fetuses; n = 4 offspring) or letrozole plus estradiol (n = 4 fetuses; n = 4 offspring). Note the difference in y-axis scale between panels (A) (fetus) and (B) (offspring). Values with different letter superscripts differ from each other at p < 0.05, fetuses; p < 0.01, offspring (ANOVA Kruskal–Wallis multiple comparison test). From Albrecht et al., 2022 [40].

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  Figure 11. Box-and-whisker plots of the percentage increase (vs. basal) in brachial-artery diameter after shear stress (A) and mean arterial blood pressure (MABP) (B) in offspring delivered to baboons untreated (5 males, 7 females) or treated with letrozole (3 males, 6 females) or letrozole plus estradiol (3 males, 7 females). Values with different letter superscripts are different from each other (p < 0.01–p < 0.02, ANOVA and Kruskal–Wallis multiple comparison test). From Albrecht et al., 2022 [40].

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  Figure 12. Proposed role of placental estrogen in promoting systemic microvascularization during fetal development and, thus, insulin sensitivity and euglycemia after birth in the offspring. From Albrecht et al., 2022 [40].