Regulation of skeletal muscle metabolism and contraction performance via teneurin-latrophilin action.

Skeletal muscle regulation is responsible for voluntary muscular movement in vertebrates. The genes of two essential proteins, teneurins and latrophilins (LPHN), evolving in ancestors of multicellular animals, form a ligand-receptor pair, and are now shown to be required for skeletal muscle function. Teneurins possess a bioactive peptide, termed the teneurin C-terminal associated peptide (TCAP) that interacts with the LPHNs to regulate skeletal muscle contractility strength and fatigue by an insulin-independent glucose importation mechanism. CRISPR-based knockouts and siRNA-associated knockdowns of LPHN-1 and-3 shows that TCAP stimulates an LPHN-mediated cytosolic Ca 2+ signal transduction cascade to increase energy metabolism and enhance skeletal muscle function via increases in type-1 oxidative fiber formation and reduce the fatigue response. Thus, the teneurin/TCAP-LPHN system is presented as a novel mechanism likely to regulate the energy requirements and performance of skeletal muscle.

Alcohol Use Disorders and Their Harmful Effects on the Contractility of Skeletal, Cardiac and Smooth Muscles

Alcohol misuse has deleterious effects on personal health, family, societal units, and global economies. Moreover, alcohol misuse usually leads to several diseases and conditions, including alcoholism, which is a chronic condition and a form of addiction. Alcohol misuse, whether as acute intoxication or alcoholism, adversely affects skeletal, cardiac and/or smooth muscle contraction. Ethanol (ethyl alcohol) is the main effector of alcohol-induced dysregulation of muscle contractility, regardless of alcoholic beverage type or the ethanol metabolite (with acetaldehyde being a notable exception). Ethanol, however, is a simple and “promiscuous” ligand that affects many targets to mediate a single biological effect. In this review, we firstly summarize the processes of excitation-contraction coupling and calcium homeostasis which are critical for the regulation of contractility in all muscle types. Secondly, we present the effects of acute and chronic alcohol exposure on the contractility of skeletal, cardiac, and vascular/ nonvascular smooth muscles. Distinctions are made between in vivo and in vitro experiments, intoxicating vs. sub-intoxicating ethanol levels, and human subjects vs. animal models. The differential effects of alcohol on biological sexes are also examined. Lastly, we show that alcohol-mediated disruption of muscle contractility, involves a wide variety of molecular players, including contractile proteins, their regulatory factors, membrane ion channels and pumps, and several signaling molecules. Clear identification of these molecular players constitutes a first step for a rationale design of pharmacotherapeutics to prevent, ameliorate and/or reverse the negative effects of alcohol on muscle contractility.

Peripheral Alterations Affect the Loss in Force after a Treadmill Downhill Run

Downhill running has an important effect on performance in trail running competitions, but it is less studied than uphill running. The purpose of this study was to investigate the cardiorespiratory response during 15 minutes of downhill running (DR) and to evaluate the neuromuscular consequences in a group of trail runners. Before and after a 15-min DR trial (slope: −25%) at ~60% of maximal oxygen consumption (V̇O2max), we evaluated maximal voluntary contraction torque (MVCt) and muscle contractility in a group of seventeen trail running athletes. Additionally, during the DR trial, we measured V̇O2 and heart rate (HR). V̇O2 and HR increased as a function of time, reaching +19.8 ± 15.9% (p < 0.001; ES: 0.49, medium) and +15.3 ± 9.9% (p < 0.001; ES: 0.55, large), respectively, in the last minute of DR. Post-exercise, the MVCt decreased (−22.2 ± 12.0%; p < 0.001; ES = 0.55, large) with respect to the pre-exercise value. All the parameters related to muscle contractility were impaired after DR: the torque evoked by a potentiated high frequency doublet decreased (−28.5 ± 12.7%; p < 0.001; ES: 0.61, large), as did the torque response from the single-pulse stimulation (St, −41.6 ± 13.6%; p < 0.001; ES: 0.70, large) and the M-wave (−11.8 ± 12.1%; p < 0.001; ES: 0.22, small). We found that after 15 min of DR, athletes had a decreased MVCt, which was ascribed mainly to peripheral rather than central alterations. Additionally, during low-intensity DR exercise, muscle fatigue and exercise-induced muscle damage may contribute to the development of O2 and HR drift.

Influence of fat infiltration, tear size, and post-operative tendon integrity on muscle contractility of repaired supraspinatus muscle

Background The purpose of this study was to evaluate the effect of fat infiltration, tear size, and post-operative tendon integrity, on post-operative contractility. Methods Thirty-five patients who underwent rotator cuff repair were included. The fat infiltration, tear size, and post-operative tendon integrity were evaluated by Goutallier stage, Cofield classification, and Sugaya classification, respectively. The muscle elasticity at rest and at contraction was assessed by real-time tissue elastography pre- and one-year post-operatively. We defined the difference in elasticity between at rest and at contraction as the activity value which reflects muscle contractility. Results The activity value in patients with Sugaya Type I tended to increase regardless of Cofield classification, whereas those with Sugaya Type III and IV tended to decrease. While the activity value in the patients classified as stage 1 and Type I tended to increase, patients classified as stage 2 showed decreased or constant in contractility even in those subjects classified as Type I. Stepwise multiple regression analysis showed both pre- (p = 0.004, r = -0.47) and post-operative activity values (p = 0.022, r = -0.39) to be significantly correlated only with the Goutallier stage. Conclusion Multiple regression analysis indicated only the Goutallier stage was a significant independent factor for contractility of the supraspinatus muscle. Supraspinatus muscle contractility in patients classified as Types III and IV based on the Sugaya classification tended to decrease post-operatively, while patients whose contractility increased post-operatively were characterized by having a Type I tendon integrity.

Molecular Mechanisms of the Deregulation of Muscle Contraction Induced by the R90P Mutation in Tpm3.12 and the Weakening of this Effect by BDM and W7

Point mutations in the genes encoding the skeletal muscle isoforms of tropomyosin can cause a range of muscle diseases. The amino acid substitution of Arg for Pro residue in the 90th position (R90P) in γ-tropomyosin (Tpm3.12) is associated with congenital fiber type disproportion and muscle weakness. The molecular mechanisms underlying muscle dysfunction in this disease remain unclear. Here, we observed that this mutation causes an abnormally high Ca2+-sensitivity of myofilaments in vitro and in muscle fibers. To determine the critical conformational changes that myosin, actin, and tropomyosin undergo during the ATPase cycle and the alterations in these changes caused by R90P replacement in Tpm3.12, we used polarized fluorimetry. It was shown that the R90P mutation inhibits the ability of tropomyosin to shift towards the outer domains of actin, which is accompanied by the almost complete depression of troponin’s ability to switch actin monomers off and to reduce the amount of the myosin heads weakly bound to F-actin at a low Ca2+. These changes in the behavior of tropomyosin and the troponin–tropomyosin complex, as well as in the balance of strongly and weakly bound myosin heads in the ATPase cycle may underlie the occurrence of both abnormally high Ca2+-sensitivity and muscle weakness. BDM, an inhibitor of myosin ATPase activity, and W7, a troponin C antagonist, restore the ability of tropomyosin for Ca2+-dependent movement and the ability of the troponin–tropomyosin complex to switch actin monomers off, demonstrating a weakening of the damaging effect of the R90P mutation on muscle contractility.