Transorgan Short-Chain Fatty Acid Fluxes in the Fasted and Postprandial State in the Pig

The short-chain fatty acids (SCFAs) acetate, propionate, butyrate, isovalerate, and valerate are end products of intestinal bacterial fermentation and important mediators in the interplay between the intestine and peripheral organs. To unravel the transorgan fluxes and mass balance comparisons of SCFAs, we measured their net fluxes across several organs in a translational pig model. In multi-catheterized conscious pigs (n=12, 25.6 (95% CI [24.2, 26.9]) kg, 8-12 weeks old), SCFA fluxes across portal drained viscera (PDV), liver, kidneys, and hindquarter (muscle compartment) were measured after an overnight fast and in the postprandial state, 4 h after administration of a fiber-free, mixed meal. PDV was the main releasing compartment of acetate, propionate, butyrate, isovalerate, and valerate during fasting and in the postprandial state (all P=0.001). Splanchnic acetate release was high due to the absence of hepatic clearance. All other SCFAs were extensively taken up by the liver (all P<0.05). Even though only 7% [4, 10] (propionate), 42% [23, 60] (butyrate), 26% [12, 39] (isovalerate), and 3% [0.4, 5] (valerate) of PDV release were excreted from the splanchnic area in the fasted state, splanchnic release of all SCFAs was significant (all P≤0.01). Splanchnic propionate, butyrate, isovalerate and valerate release remained low but significant in the postprandial state (all P<0.01). We identified muscle and kidneys as main peripheral SCFA metabolizing organs, taking up the majority of all splanchnically released SCFAs in the fasted state and in the postprandial state. We conclude that the PDV is the main SCFA releasing and the liver the main SCFA metabolizing organ. Splanchnically released SCFAs appear to be important energy substrates to peripheral organs not only in the fasted but also in the postprandial state.

Muscle Homeostasis and Regeneration: From Molecular Mechanisms to Therapeutic Opportunities

The capacity of adult muscle to regenerate in response to injury stimuli represents an important homeostatic process. Regeneration is a highly coordinated program that partially recapitulates the embryonic developmental program and involves the activation of the muscle compartment of stem cells, namely satellite cells, as well as other precursor cells, whose activity is strictly dependent on environmental signals. However, muscle regeneration is severely compromised in several pathological conditions due to either the progressive loss of stem cell populations or to missing signals that limit the damaged tissues from efficiently activating a regenerative program. It is, therefore, plausible that the loss of control over these cells’ fate might lead to pathological cell differentiation, limiting the ability of a pathological muscle to sustain an efficient regenerative process. This Special Issue aims to bring together a collection of original research and review articles addressing the intriguing field of the cellular and molecular players involved in muscle homeostasis and regeneration and to suggest potential therapeutic approaches for degenerating muscle disease.

Arboviruses and Muscle Disorders: From Disease to Cell Biology

Infections due to arboviruses (arthropod-borne viruses) have dramatically increased worldwide during the last few years. In humans, symptoms associated with acute infection of most arboviruses are often described as “dengue-like syndrome”, including fever, rash, conjunctivitis, arthralgia, and muscular symptoms such as myalgia, myositis, or rhabdomyolysis. In some cases, muscular symptoms may persist over months, especially following flavivirus and alphavirus infections. However, in humans the cellular targets of infection in muscle have been rarely identified. Animal models provide insights to elucidate pathological mechanisms through studying viral tropism, viral-induced inflammation, or potential viral persistence in the muscle compartment. The tropism of arboviruses for muscle cells as well as the viral-induced cytopathic effect and cellular alterations can be confirmed in vitro using cellular models. This review describes the link between muscle alterations and arbovirus infection, and the underlying mechanisms.

An Hourglass Circuit Motif Transforms a Motor Program via Subcellularly Localized Calcium Signaling in Muscle

Neural control of muscle function is fundamental to animal behavior. In many cases, specific muscles can generate multiple distinct behaviors. Nonetheless, individual muscle cells are generally regarded as the smallest units of motor control. Here we report that muscle cells can alter their behavioral output by contracting subcellularly. We previously discovered that noxious tastes reverse the flow of material through the C. elegans pharynx, a neuromuscular pump, resulting in spitting. We now show that spitting is driven by the contraction of subcellular regions of individual muscle cells. Localized calcium signals accompany these contractions. Spitting is controlled by an “hourglass” circuit motif: parallel neural pathways converge onto a single motor neuron that differentially controls multiple muscles and the critical subcellular muscle compartment. In short, we find that subcellular muscle units enable modulatory motor control and propose that subcellular muscle contraction is a fundamental mechanism by which neurons can reshape motor function.

Necrotizing Fasciitis Causing Acute Compartment Syndrome after Radial Artery Catheterization

Necrotizing fasciitis is a rare but potentially fatal infection involving the subcutaneous tissue and fascia with the development of necrosis of these structures. Acute compartment syndrome occurs when increased pressure within a closed muscle compartment compromises the circulation and function of the tissues within that space. We report the case of a male patient who was admitted to the intensive care unit for the management of urosepsis due to an acute obstructive pyelonephritis complicated by cardiopulmonary arrest. A radial arterial catheter in the left arm was urgently inserted, under suboptimal aseptic technique. His clinical condition progressively deteriorated, and swelling of the left arm with extension to the forearm with incipient signs of compromised perfusion were observed. The diagnosis of necrotizing fasciitis with acute compartment syndrome was made and an emergency fasciectomy performed. Following this, the patient gradually improved, organ dysfunction resolved, and he was discharged without sequelae.

Periodicity, time constants of drainage, and the mechanical determinants of peak cardiac output during exercise

To analyze mechanical adaptations that must occur in the cardiovascular system to reach the high cardiac outputs known to occur at peak aerobic performance, we adapted a computational model of the circulation by adding a second parallel venous compartment as proposed by August Krogh in 1912. One venous compartment has a large compliance and slow time constant of emptying; it is representative of the splanchnic circulation. The other has a low compliance and fast time constant of emptying and is representative of muscle beds. Fractional distribution between the two compartments is an important determinant of cardiac output. Parameters in the model were based on values from animal and human studies normalized to a 70 kg male. The baseline cardiac output was set at 5 L/min, and we aimed for 25 L/min at peak exercise with a fractional flow to the peripheral-muscle region of 90%. Finally, we added the equivalent of a muscle pump. Adjustments in circuit and cardiac parameters alone increased cardiac output to only 15.6 L/min because volume accumulated in the muscle compartment and limited a higher cardiac output. Addition of muscle contractions decompressed the muscle region and allowed cardiac output to increase to 23.4 L/min. The pulsatility of blood flow imposes important constraints on the adaptations of cardiac and circulatory functions because it fixes the times for filling and emptying. Flow is further limited by the limits of cardiac filling on each beat. Muscle contractions play a key role by decompressing volume that would otherwise accumulate in the muscle vasculature and by decreasing the time for stroke return to the right ventricle. NEW & NOTEWORTHY We used a computational model of the circulation and previous human and animal data to model mechanical changes in the heart and circulation that are needed to reach the known high cardiac output at peak aerobic exercise. Key points are that time constants of drainage of circulatory compartments put limits on peak flow in a pulsatile system. Muscle contractions increase the rate of return to the heart and by doing so prevent accumulation of volume in the muscle compartment and greatly increase circulatory capacity.