Regenerated Microvascular Networks in Ischemic Skeletal Muscle

Skeletal muscle is the largest organ in humans. The viability and performance of this metabolically demanding organ are exquisitely dependent on the integrity of its microcirculation. The architectural and functional attributes of the skeletal muscle microvasculature are acquired during embryonic and early postnatal development. However, peripheral vascular disease in the adult can damage the distal microvasculature, together with damaging the skeletal myofibers. Importantly, adult skeletal muscle has the capacity to regenerate. Understanding the extent to which the microvascular network also reforms, and acquires structural and functional competence, will thus be critical to regenerative medicine efforts for those with peripheral artery disease (PAD). Herein, we discuss recent advances in studying the regenerating microvasculature in the mouse hindlimb following severe ischemic injury. We highlight new insights arising from real-time imaging of the microcirculation. This includes identifying otherwise hidden flaws in both network microarchitecture and function, deficiencies that could underlie the progressive nature of PAD and its refractoriness to therapy. Recognizing and overcoming these vulnerabilities in regenerative angiogenesis will be important for advancing treatment options for PAD.

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The Evolution of Blood Flow Restricted Exercise

Frontiers in Physiology ◽

10.3389/fphys.2021.747759 ◽

2021 ◽

Vol 12 ◽

Author(s):

Eduardo D. S. Freitas ◽

Murat Karabulut ◽

Michael G. Bemben

Keyword(s):

Skeletal Muscle ◽

Blood Flow ◽

Flow Restriction ◽

Alternative Approach ◽

Safe Technique ◽

Mechanisms Of Adaptation ◽

Artery Disease ◽

Heavy Loads ◽

And Function ◽

External Loads

The use of blood flow restricted (BFR) exercise has become an accepted alternative approach to improve skeletal muscle mass and function and improve cardiovascular function in individuals that are not able to or do not wish to use traditional exercise protocols that rely on heavy loads and high training volumes. BFR exercise involves the reduction of blood flow to working skeletal muscle by applying a flexible cuff to the most proximal portions of a person’s arms or legs that results in decreased arterial flow to the exercising muscle and occluded venous return back to the central circulation. Safety concerns, especially related to the cardiovascular system, have not been consistently reported with a few exceptions; however, most researchers agree that BFR exercise can be a relatively safe technique for most people that are free from serious cardiovascular disease, as well as those with coronary artery disease, and also for people suffering from chronic conditions, such as multiple sclerosis, Parkinson’s, and osteoarthritis. Potential mechanisms to explain the benefits of BFR exercise are still mostly speculative and may require more invasive studies or the use of animal models to fully explore mechanisms of adaptation. The setting of absolute resistive pressures has evolved, from being based on an individual’s systolic blood pressure to a relative measure that is based on various percentages of the pressures needed to totally occlude blood flow in the exercising limb. However, since several other issues remain unresolved, such as the actual external loads used in combination with BFR, the type of cuff used to induce the blood flow restriction, and whether the restriction is continuous or intermittent, this paper will attempt to address these additional concerns.

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Canonical NF-κB signaling regulates satellite stem cell homeostasis and function during regenerative myogenesis

Journal of Molecular Cell Biology ◽

10.1093/jmcb/mjy053 ◽

2018 ◽

Vol 11 (1) ◽

pp. 53-66 ◽

Cited By ~ 3

Author(s):

Alex R Straughn ◽

Sajedah M Hindi ◽

Guangyan Xiong ◽

Ashok Kumar

Keyword(s):

Skeletal Muscle ◽

Satellite Cell ◽

Satellite Cells ◽

Muscle Regeneration ◽

Cell Function ◽

Skeletal Muscle Regeneration ◽

Cell Homeostasis ◽

Adult Skeletal Muscle ◽

Adult Mice ◽

And Function

Abstract Skeletal muscle regeneration in adults is attributed to the presence of satellite stem cells that proliferate, differentiate, and eventually fuse with injured myofibers. However, the signaling mechanisms that regulate satellite cell homeostasis and function remain less understood. While IKKβ-mediated canonical NF-κB signaling has been implicated in the regulation of myogenesis and skeletal muscle mass, its role in the regulation of satellite cell function during muscle regeneration has not been fully elucidated. Here, we report that canonical NF-κB signaling is induced in skeletal muscle upon injury. Satellite cell-specific inducible ablation of IKKβ attenuates skeletal muscle regeneration in adult mice. Targeted ablation of IKKβ also reduces the number of satellite cells in injured skeletal muscle of adult mice, potentially through inhibiting their proliferation and survival. We also demonstrate that the inhibition of specific components of the canonical NF-κB pathway causes precocious differentiation of cultured satellite cells both ex vivo and in vitro. Finally, our results highlight that the constitutive activation of canonical NF-κB signaling in satellite cells also attenuates skeletal muscle regeneration following injury in adult mice. Collectively, our study demonstrates that the proper regulation of canonical NF-κB signaling is important for the regeneration of adult skeletal muscle.

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mTORC2 affects the maintenance of the muscle stem cell pool

Skeletal Muscle ◽

10.1186/s13395-019-0217-y ◽

2019 ◽

Vol 9 (1) ◽

Cited By ~ 1

Author(s):

Nathalie Rion ◽

Perrine Castets ◽

Shuo Lin ◽

Leonie Enderle ◽

Judith R. Reinhard ◽

...

Keyword(s):

Skeletal Muscle ◽

Mammalian Target Of Rapamycin ◽

Adult Skeletal Muscle ◽

Muscle Stem Cells ◽

And Function ◽

Muscle Homeostasis ◽

Biological Methods

Abstract Background The mammalian target of rapamycin complex 2 (mTORC2), containing the essential protein rictor, regulates cellular metabolism and cytoskeletal organization by phosphorylating protein kinases, such as PKB/Akt, PKC, and SGK. Inactivation of mTORC2 signaling in adult skeletal muscle affects its metabolism, but not muscle morphology and function. However, the role of mTORC2 in adult muscle stem cells (MuSCs) has not been investigated. Method Using histological, biochemical, and molecular biological methods, we characterized the muscle phenotype of mice depleted for rictor in the Myf5-lineage (RImyfKO) and of mice depleted for rictor in skeletal muscle fibers (RImKO). The proliferative and myogenic potential of MuSCs was analyzed upon cardiotoxin-induced injury in vivo and in isolated myofibers in vitro. Results Skeletal muscle of young and 14-month-old RImyfKO mice appeared normal in composition and function. MuSCs from young RImyfKO mice exhibited a similar capacity to proliferate, differentiate, and fuse as controls. In contrast, the number of MuSCs was lower in young RImyfKO mice than in controls after two consecutive rounds of cardiotoxin-induced muscle regeneration. Similarly, the number of MuSCs in RImyfKO mice decreased with age, which correlated with a decline in the regenerative capacity of mutant muscle. Interestingly, reduction in the number of MuSCs was also observed in 14-month-old RImKO muscle. Conclusions Our study shows that mTORC2 signaling is dispensable for myofiber formation, but contributes to the homeostasis of MuSCs. Loss of mTORC2 does not affect their myogenic function, but impairs the replenishment of MuSCs after repeated injuries and their maintenance during aging. These results point to an important role of mTORC2 signaling in MuSC for muscle homeostasis.

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Localization and function of Xinα in mouse skeletal muscle

AJP Cell Physiology ◽

10.1152/ajpcell.00005.2013 ◽

2013 ◽

Vol 304 (10) ◽

pp. C1002-C1012 ◽

Cited By ~ 10

Author(s):

Han-Zhong Feng ◽

Qinchuan Wang ◽

Rebecca S. Reiter ◽

Jenny L.-C. Lin ◽

Jim J.-C. Lin ◽

...

Keyword(s):

Skeletal Muscle ◽

Heart Development ◽

Neuromuscular Junctions ◽

Troponin T ◽

Diaphragm Muscle ◽

Myotendinous Junction ◽

Wild Type ◽

Adult Skeletal Muscle ◽

Edl Muscle ◽

And Function

The Xin repeat-containing proteins were originally found in the intercalated discs of cardiac muscle with implicated roles in cardiac development and function. A pair of paralogous genes, Xinα ( Xirp1) and Xinβ ( Xirp2), is present in mammals. Ablation of the mouse Xinα ( mXinα) did not affect heart development but caused late-onset adulthood cardiac hypertrophy and cardiomyopathy with conductive defects. Both mXinα and mXinβ are also found in the myotendinous junction (MTJ) of skeletal muscle. Here we investigated the structural and functional significance of mXinα in skeletal muscle. In addition to MTJ and the contact sites between muscle and perimysium, mXinα but not mXinβ was found in the blood vessel walls, whereas both proteins were absent in neuromuscular junctions and nerve fascicles. Coimmunoprecipitation suggested association of mXinα with talin, vinculin, and filamin, but not β-catenin, in adult skeletal muscle, consistent with our previous report of colocalization of mXinα with vinculin. Loss of mXinα in mXinα-null mice had subtle effects on the MTJ structure and the levels of several MTJ components. Diaphragm muscle of mXinα-null mice showed hypertrophy. Compared with wild-type controls, mouse extensor digitorum longus (EDL) muscle lacking mXinα exhibited no overt change in contractile and relaxation velocities or maximum force development but better tolerance to fatigue. Loaded fatigue contractions generated stretch injury in wild-type EDL muscle as indicated by a fragmentation of troponin T. This effect was blunted in mXinα-null EDL muscle. The results suggest that mXinα play a role in MTJ conductance of contractile and stretching forces.

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Effect of Aging on the Structure and Function of Skeletal Muscle Microvascular Networks

Microcirculation ◽

10.1080/10739680600618892 ◽

2006 ◽

Vol 13 (4) ◽

pp. 279-288 ◽

Cited By ~ 24

Author(s):

Shawn E. Bearden

Keyword(s):

Skeletal Muscle ◽

Structure And Function ◽

Microvascular Networks ◽

And Function

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Biodegradable coronary scaffolds: their future and clinical and technological challenges

Cardiovascular Research ◽

10.1093/cvr/cvy097 ◽

2018 ◽

Vol 114 (8) ◽

pp. 1063-1072 ◽

Cited By ~ 9

Author(s):

Jarkko P Hytönen ◽

Jouni Taavitsainen ◽

Santeri Tarvainen ◽

Seppo Ylä-Herttuala

Keyword(s):

Treatment Options ◽

Current Treatment ◽

Metallic Stent ◽

Elastic Recoil ◽

Biological Responses ◽

Technological Advances ◽

Increased Risk ◽

Artery Disease ◽

And Function

Abstract Angioplasty and stenting are standard treatment options for both stabile occlusive coronary artery disease and acute myocardial infarctions. Over the last years, several biodegradable stent systems have entered pre-clinical and clinical evaluation and into clinical practice. A strong supporting scaffold is necessary after angioplasty to prevent elastic recoil of the vessel but in the long term a permanent metallic stent will only impair normal physiology of the artery wall. Thus, the main advantage of a resorbable system is the potential for better vessel recovery and function in the long term. The new stent systems differ from traditional stents in size and biological responses and questions have risen regarding their mechanical strength and increased risk of stent thrombosis. Here, we present current treatment options with biodegradable scaffolds, discuss further key areas for improvements and review novel technological advances in the context of all up-to-date clinical trial information. New material choices are also covered as well as special considerations for pre-clinical testing.

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Surgery for Lung Cancer and the Consequences for the Swallow

Perspectives of the ASHA Special Interest Groups ◽

10.1044/persp1.sig13.162 ◽

2016 ◽

Vol 1 (13) ◽

pp. 162-168

Author(s):

Pippa Hales ◽

Corinne Mossey-Gaston

Keyword(s):

Lung Cancer ◽

Treatment Options ◽

Vocal Cord Palsy ◽

Subsequent Treatment ◽

Physiological Reserve ◽

Palliative Phase ◽

And Function ◽

The Impact ◽

Swallow Function

Lung cancer is one of the most commonly diagnosed cancers across Northern America and Europe. Treatment options offered are dependent on the type of cancer, the location of the tumor, the staging, and the overall health of the person. When surgery for lung cancer is offered, difficulty swallowing is a potential complication that can have several influencing factors. Surgical interaction with the recurrent laryngeal nerve (RLN) can lead to unilateral vocal cord palsy, altering swallow function and safety. Understanding whether the RLN has been preserved, damaged, or sacrificed is integral to understanding the effect on the swallow and the subsequent treatment options available. There is also the risk of post-surgical reduction of physiological reserve, which can reduce the strength and function of the swallow in addition to any surgery specific complications. As lung cancer has a limited prognosis, the clinician must also factor in the palliative phase, as this can further increase the burden of an already compromised swallow. By understanding the surgery and the implications this may have for the swallow, there is the potential to reduce the impact of post-surgical complications and so improve quality of life (QOL) for people with lung cancer.

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