我们感谢利亚姆泰伦的专家阅读手稿。这项工作得到了加拿大自然科学和工程研究委员会 (NSERC) 对检察官的资助。检察官胡德也是一个加拿大研究椅子在细胞生理学的持有者。

所有与动物有关的程序都经过约克大学动物保护委员会的审查和批准。在抵达约克大学的动物设施, 所有的老鼠被给予至少五天, 适应到他们的环境之前, 在手术过程中, 与食物提供的ad 随意。虽然此协议已被应用于其他物种15,17,22, 目前的论文建立在 Pette 和同事们的开创性工作23上, 并着重于大鼠模型, 特别是。
1. 慢性收缩活动单位的制备
<ol><li>使用电压表, 检查硬币锂电池的潜力。 注: 每个电池的电位应为3.0 ± 0.10 v</li>
	<li>将两个或三电池插入单元的插槽中, 使总电位为 6-9 v 注意: 这是由研究人员斟酌决定在整个实验过程中保持多少潜能 (6 或9伏)。根据研究的设计和预期的刺激强度, 可以使用2或3电池。</li>
	<li>通过脉冲指示器验证该单元是否正常工作, 将该单元暴露为便携式红外线闪光灯发出的1脉冲。</li>
</ol>2. 慢性收缩活动的手术方法
注: 在手术前对所有手术工具进行消毒。在手术后和术后立即, 大鼠的体温由加热垫维持。在外科手术的褶皱上进行手术是可取的。外科医生应该戴上无菌的外科手套以及干净的实验室大衣。如有需要, 建议佩戴一次性口罩。
<ol><li>1-3% 异氟醚吸入氧麻醉大鼠, 由气体汽化器系统操作。确认动物是完全镇静通过检查后肢脚趾捏和观察呼吸深度和速率。将眼部润滑剂涂抹在眼睛上, 避免干燥。应用皮下注射昔 (0.5 毫克/毫升) 在2毫克/千克。 注意: 它也建议有一个多模态应用的镇痛 (如, 昔加利多卡因), 以减少任何疼痛期间和手术后。</li>
	<li>轻轻地剃去左后肢, 以及从颈部后面的躯干, 在前肢后面和胸前。用碘和乙醇轻轻擦拭剃光区域消毒。</li>
	<li>与动物躺在它的胃, 做一个小切口 (〜0.5 厘米), 在颈部背部的中心, 剃光区域 (在肩胛骨之间的可触及区域) 使用手术刀 (No. 10 刀片)。</li>
	<li>找到腓总神经。<ol>
<li>将动物卷到右侧, 在左后肢的皮肤上做一个 2-3 厘米长的切口。靶切口区域周围的大腿上部肌肉组是地标之间的酒窝的膝盖关节和背部接近的起源的尾巴。 注意: 在改变身体位置时, 要注意不要污染第一个切口区域。</li>
		<li>使用钝尖的弯曲手术剪刀, 解剖皮下面积广泛〜 3.5-4 厘米, 分离皮肤的基础肌肉, 以使一个口袋之间打开的皮肤和潜在的肌肉。在切口的整个圆周周围打开皮肤 (~ 1.5 厘米2)。</li>
		<li>做一个小切口 (少于0.5 厘米) 对肱二头肌肌肉与外科剪刀, 确保剪刀的秘诀是直接削减通过肌肉。</li>
		<li>轻轻打开切口区域, 直到内部肌肉组和腓总神经可见 (外部肌肉组织 (即,股二头肌) 的深度约为0.5 厘米)。使用镊子, 轻轻触摸/捏的可见神经和观察的目标肌肉群 (如, TA 肌肉) 和脚趾 (可见背) 的反应, 以确认腓总神经是孤立的。 注意: 这一步应该采取极端谨慎的做法, 以避免切割或损害神经。</li>
		<li>用金属器打开窗口, 使窗口的大小为1.5 厘米2 , 而腓神经位于窗口的中心。使用连接到表面 (或手术板) 的带和/或橡皮筋的小金属钩 (图 2A)。</li>
	</ol></li>
	<li>把电线连接到神经的两侧。<ol>
<li>准备〜 50-60 厘米聚四氟乙烯 (PTFE) 涂层精细不锈钢线, 并对折它一半。 注意: 在手术前, 在紫外线照射下暴露 PTFA 涂层的导线可能会有帮助。</li>
		<li>将铁丝的折叠部分钩入30厘米长的不锈钢棒的狭缝中。通过杆, 连同导线, 从后肢的开放口袋的皮下向小切口区域在后面的颈部, 在 L 形模式上的腿和沿背部的中心。</li>
		<li>在后肢找到导线的两端。因为所有的电线都是聚四氟乙烯绝缘的, 所以要剥线。使用手术刀, 小心地剥去铁丝的两端1.5 厘米。如果电线磨损, 把它们切掉, 再重新带上。包裹剥线结束周围一个钝21克针 (5 次), 使线圈。一旦线圈是正确的, 松开他们的针头。</li>
		<li>使用大小6-0 的外科手术丝, 确保腓总神经两侧两侧的线圈 (图 2A)。<ol>
<li>在线圈的末端做一个结, 并且缝合它在神经的左手边。确保线圈是从神经的 1.5-2.5 毫米。</li>
			<li>为了保证线圈的安全, 在线圈上应用两个或三条附加的缝合线。</li>
			<li>在神经的右手边重复这些步骤。</li>
		</ol>
</li>
		<li>应用 2-3 滴抗生素溶液 (氨苄西林生理盐水; 132 毫克/毫升), 然后仔细缝合窗口 (即,肱二头肌组织) 使用大小5-0 丝绸。</li>
	</ol></li>
	<li>松散的风剩余的电线 (约直径的食指) 和推入皮下的口袋上方的缝合切口的二头肌肌肉 (约在臀部)。</li>
	<li>再次应用 2-3 滴抗生素溶液 (生理盐水中的氨苄西林; 132 毫克/毫升)。通过装订关闭打开的皮肤。</li>
	<li>将导线 (从颈部的切口区域出来) 连接到共同评估刺激器。<ol>
<li>将针脚插座与电线连接。<ol>
<li>切断从颈部顶端的切口的导线回路, 以创建2线端 (这些导线通向腓神经两侧缝合的线圈)。</li>
			<li>使用手术刀, 剥去电线的两端0.5 厘米, 切断磨损的电线, 如果有的话。</li>
			<li>将导线的剥离部分慢慢地推入销钉插座的孔中, 并使用烙铁, 将针脚插座上的导线焊上。</li>
		</ol>
</li>
		<li>(可选) 检查电线的连接。<ol>
<li>通过鳄鱼夹子将针脚连接到大型台式刺激器单元。</li>
			<li>提供一个9伏 (0.1 毫秒, 10 赫兹) 的单脉冲, 以确认 TA 肌肉收缩和左脚 dorsiflexes。</li>
		</ol>
</li>
		<li>通过针连接线两端通过无菌纱布垫, 是〜 4 cm x 4 厘米。</li>
		<li>将针脚连接到共同国家评估刺激装置。<ol>
<li>通过在刺激盒底部的孔导线。 注: 此框为共同国家评估刺激单元的家庭制作室, 3.5 cm x 3.5 cm x 2.5 cm13。</li>
			<li>将针脚插入到共同国家评估单位的连接插座中。将共同国家评估单位轻轻放进会议厅。使用粘性的粘性, 以确保在会议厅底部的共同国家评估单位。</li>
		</ol>
</li>
		<li>使用运动胶带或多孔的外科手术带, 在剃光的躯干周围用胶带固定房间。关闭的顶部三层的录音和完成通过包装在刺激盒两侧的磁带, 以确保框 (图 2B)。</li>
	</ol></li>
	<li>检查共同国家评估是否在工作, 将该单位暴露在一个单脉冲红外光 (波长频谱 > 770 nm), 这是由便携式红外线闪光灯发射。 注: 如果共同国家评估工作正常, 研究人员将能够看到后肢肌肉 (即, TA) 是为了响应红外线而收缩的。</li>
	<li>观察鼠并监测它的温度, 直到它完全恢复知觉。将其放在单人笼内, 以防止其他动物受到任何伤害, 并在余下的研究中不留任何隧道或塑料物件, 以减轻对刺激装置或动物造成损害的危险。供应含阿莫西林的水瓶 (0.5 毫克/毫升)。</li>
	<li>1毫克/千克剂量的昔皮下每24小时的手术后, 至少持续72小时。</li>
</ol>3. 慢性收缩活动
<ol><li>手术后, 允许至少 5-7 天, 以充分恢复切口和缝合区/周围的骨骼肌肉。 注意: 在评估过程中和之后, 通过观察它们的行为 (例如,进食、饮酒和/或移动), 彻底检查每种动物的状况。此外, 通过检查在共同国家评估程序之前和之后的体重变化来确定任何严重的压力或不良影响。</li>
	<li>在共同国家评估的刺激之日, 通过便携式红外线闪光灯将刺激装置暴露在单一的红外线脉冲 (波长范围 > 770 nm) 上, 打开共同国家评估。</li>
	<li>应用3或 6 h 的10赫兹共同国家评估刺激。 注: 刺激的时间范围由研究员负责。在这些实验中, 刺激的频率从未改变过, 在我们的经验中, 通过将刺激从3延长到6小时, 在线粒体适应方面只有非常适度的增强。如果可能的话, 检查刺激和动物每 30-60 分钟。</li>
	<li>在预期的共同国家评估期之后, 通过红外线曝光 (与在单位上打开相同的程序) 关闭共同国家评估单位。</li>
	<li>如果应用多天, 请重复步骤3.2。到3.4。</li>
	<li>确定组织收集的时间。例如, 收集组织24小时后, 在最后一回合的共同国家评估 (即, 18 小时后, 最后的共同国家评估刺激的6小时), 这是在麻醉下进行的, 在共同评估的手术过程中进行。在收集所有的组织, 安乐动物通过切除心脏, 而动物仍在麻醉。</li>
</ol>

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A. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Regulation+of+the+autophagy+system+during+chronic+contractile+activity-induced+muscle+adaptations.">Regulation of the autophagy system during chronic contractile activity-induced muscle adaptations.</a> Physiol Rep. 5 (14), (2017).</li><li>Memme, J. M., Oliveira, A. N., Hood, D. 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A., Pette, D. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Species-specific+effects+of+chronic+nerve+stimulation+upon+tibialis+anterior+muscle+in+mouse,+rat,+guinea+pig,+and+rabbit.">Species-specific effects of chronic nerve stimulation upon tibialis anterior muscle in mouse, rat, guinea pig, and rabbit.</a> Pflugers Arch. 412 (1-2), 86-92 (1988).</li><li>Ohlendieck, K., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Effects+of+chronic+low-frequency+stimulation+on+Ca2+-regulatory+membrane+proteins+in+rabbit+fast+muscle.">Effects of chronic low-frequency stimulation on Ca2+-regulatory membrane proteins in rabbit fast muscle.</a> Pflugers Arch. 438 (5), 700-708 (1999).</li><li>Brown, M. D., Cotter, M. A., Hudlicka, O., Vrbova, G. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=The+effects+of+different+patterns+of+muscle+activity+on+capillary+density,+mechanical+properties+and+structure+of+slow+and+fast+rabbit+muscles.">The effects of different patterns of muscle activity on capillary density, mechanical properties and structure of slow and fast rabbit muscles.</a> Pflugers Arch. 361 (3), 241-250 (1976).</li><li>Skorjanc, D., Traub, I., Pette, D. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Identical+responses+of+fast+muscle+to+sustained+activity+by+low-frequency+stimulation+in+young+and+aging+rats.">Identical responses of fast muscle to sustained activity by low-frequency stimulation in young and aging rats.</a> J Appl Physiol. 85 (2), 437-441 (1998).</li><li>Kim, Y., Triolo, M., Hood, D. A. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Impact+of+Aging+and+Exercise+on+Mitochondrial+Quality+Control+in+Skeletal+Muscle.">Impact of Aging and Exercise on Mitochondrial Quality Control in Skeletal Muscle.</a> Oxid Med Cell Longev. 2017, 3165396 (2017).</li><li>Callewaert, L., Puers, B., Sansen, W., Jarvis, J. C., Salmons, S. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Programmable+implantable+device+for+investigating+the+adaptive+response+of+skeletal+muscle+to+chronic+electrical+stimulation.">Programmable implantable device for investigating the adaptive response of skeletal muscle to chronic electrical stimulation.</a> Med Biol Eng Comput. 29 (5), 548-553 (1991).</li><li>Kern, H., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Electrical+stimulation+counteracts+muscle+decline+in+seniors.">Electrical stimulation counteracts muscle decline in seniors.</a> Front Aging Neurosci. 6, 189 (2014).</li><li>Zampieri, S., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Physical+exercise+in+aging+human+skeletal+muscle+increases+mitochondrial+calcium+uniporter+expression+levels+and+affects+mitochondria+dynamics.">Physical exercise in aging human skeletal muscle increases mitochondrial calcium uniporter expression levels and affects mitochondria dynamics.</a> Physiol Rep. 4 (24), (2016).</li></ol>

作者没有什么可透露的。

慢性收缩活动 (共同国家评估) 模型的运动, 通过低频肌肉刺激在体内, 是一个优秀的模型研究肌肉表型适应锻炼13,24,25,26. 如前面的研究中所示,20,27, 共同国家评估是一个有效的工具, 研究人员可以控制训练量和频率 (即时间和天数), 并调查各种?...

骨骼肌肉可以适应运动训练, 通过改变其生物和物理结构1。耐力训练带来的主要改变之一是线粒体生物, 可以通过增加线粒体成分的表达 (例如,细胞色素 c 氧化酶 [COX] 亚基) 来评估, 以及表达转录因子, PGC-1α2。越来越多的研究表明, 许多其他因素, 包括线粒体翻转和 mitophagy, 也是重要的肌肉适应。然而, 急性或慢性运动在骨骼肌中调节这些过程的机制还不清楚。
为了描述调节运动性肌肉适应的途径, 各种运动模式在啮齿类动物研究中普遍使用, 包括跑步机、跑步轮和游泳运动。但是, 这些协议有一些限制, 因为需要 4-12 周来观察这些表型变化3,4,5。作为一种替代实验方法, 低频刺激引起的慢性收缩活动 (共同国家评估) 得到了有效的使用, 因为它可以导致肌肉适应在一个极短的时期 (即, 7 天), 其影响似乎与其他运动协议相比, 甚至更大。此外, 荷尔蒙6、温度7和神经效应8的存在可能使人们难以理解针对慢性运动的肌肉特异性反应。例如, 甲状腺激素9,10和胰岛素样生长因子 (igf-i)-111已被确定, 以调停训练诱导肌肉适应, 这也可能调节其他信号通路的骨骼肌肉.值得注意的是, 由全身因素对共同国家评估产生的影响进行了最低限度的调节, 使重点放在骨骼肌对收缩活动的直接反应上。
外部单位为共同国家评估首先介绍了由泰勒和怀特12, 并且已经开发了以修改12。简而言之, 该装置由三主要部件组成: 红外线探测器, 可通过接触红外线、脉冲发生器和脉冲指示器 (图 1) 打开和关闭。该刺激器单元的详细电路设计已在前面介绍过13。在许多审阅文章14、15、16、17中, 可以更深入地发现共同国家评估的详细和具体功能。简言之, 刺激协议的目的是激活腓总神经在低频 (即, 10 Hz), 和支配肌肉 (胫骨前 [TA] 和伸肌肌腱长长 [EDL] 肌肉) 被迫合同为预定的时间长度 (例如, 3-6 h)。随着时间的推移, 这将上述的肌肉转移到一个更有氧的表型, 显示了增加的毛细管密度18和线粒体内容19,20,21。因此, 这种方法是一个经验证的模型, 模仿一些主要的耐力训练适应大鼠骨骼肌中。
本文介绍了电极植入术的详细过程, 以使其在运动研究中得以应用。共同国家评估是研究肌肉适应时间过程的一个很好的模型, 从而为在运动训练开始后的早期和后期的各种分子和信号事件的研究提供了一个有效的工具。

<table>
	<tbody>
		<tr>
			<td>Sprague Dawley Rat</td>
			<td>Charles River</td>
			<td>Strain 400</td>
			<td></td>
		</tr>
		<tr>
			<td>Chronic contractile activity unit</td>
			<td>Home-made</td>
			<td>n/a</td>
			<td></td>
		</tr>
		<tr>
			<td>CCA unit protective box (3.5 x 3.5 x 2.5 cm)</td>
			<td>Home-made</td>
			<td>n/a</td>
			<td>Box should be made of opaque material or covered in an opague tape</td>
		</tr>
		<tr>
			<td>Coin lithium ion batteries (3V)</td>
			<td>Panasonic</td>
			<td>CR2016</td>
			<td></td>
		</tr>
		<tr>
			<td>Medwire</td>
			<td>Leico Industries</td>
			<td>316SS7/44T</td>
			<td></td>
		</tr>
		<tr>
			<td>Solder pin (socket)</td>
			<td>Digi-Key</td>
			<td>ED6218-ND</td>
			<td></td>
		</tr>
		<tr>
			<td>Zonas porous tape</td>
			<td>Johnson &#38; Johnson</td>
			<td>5104</td>
			<td></td>
		</tr>
		<tr>
			<td>Suture silk (Size 5)</td>
			<td>Ethicon</td>
			<td>640G</td>
			<td></td>
		</tr>
		<tr>
			<td>Suture silk (Size 6)</td>
			<td>Ethicon</td>
			<td>706G</td>
			<td></td>
		</tr>
		<tr>
			<td>Curved blunt scissor (11.5 cm Length)</td>
			<td>F.S.T.</td>
			<td>14075-11</td>
			<td></td>
		</tr>
		<tr>
			<td>Curved blunt scissor (15 cm Length)</td>
			<td>F.S.T.</td>
			<td>14111-15</td>
			<td></td>
		</tr>
		<tr>
			<td>Delicate haemostatic forceps (16 cm Length)</td>
			<td>Lawton</td>
			<td>06-0230</td>
			<td></td>
		</tr>
		<tr>
			<td>Scalpel</td>
			<td>Feather</td>
			<td>3</td>
			<td></td>
		</tr>
		<tr>
			<td>Curved forceps</td>
			<td>F.S.T.</td>
			<td>11052-10</td>
			<td></td>
		</tr>
		<tr>
			<td>Stainless-steel rod (30 cm; 7mm diameter)</td>
			<td>Home-made</td>
			<td>n/a</td>
			<td>Rod should have 5 mm slit in one end to hold the wire for tunneling under the skin</td>
		</tr>
		<tr>
			<td>Clip applying forceps</td>
			<td>KLS Martin</td>
			<td>20-916-12</td>
			<td></td>
		</tr>
		<tr>
			<td>Staples (clips)</td>
			<td>Bbraun</td>
			<td>BN507R</td>
			<td></td>
		</tr>
		<tr>
			<td>Metal hooks/retractor</td>
			<td>Home-made</td>
			<td>n/a</td>
			<td></td>
		</tr>
		<tr>
			<td>Povidone-iodine (500 mL)</td>
			<td>Rougier</td>
			<td>#NPN00172944</td>
			<td></td>
		</tr>
		<tr>
			<td>Ampicillin sodium</td>
			<td>Novopharm</td>
			<td>#DIN00872644</td>
			<td></td>
		</tr>
		<tr>
			<td>Metacam</td>
			<td>Boehringer</td>
			<td>#DIN02240463</td>
			<td></td>
		</tr>
		<tr>
			<td>Digital multimeter (voltmeter)</td>
			<td>Soar Corporation</td>
			<td>ME-501</td>
			<td></td>
		</tr>
		<tr>
			<td>LED digital stroboscope</td>
			<td>Lutron Electronic Enterprise</td>
			<td>DT-2269</td>
			<td></td>
		</tr>
	</tbody>
</table>

application of chronic stimulation to study contractile activity-induced rat skeletal muscle phenotypic adaptations

骨骼肌是一种高度适应性的组织, 因为它的生物化学和生理特性在对慢性运动的反应中有很大的改变。为了研究导致各种肌肉适应的基本机制, 在动物研究中使用了许多运动协议, 如跑步机、轮子跑步和游泳练习。然而, 这些运动模型需要很长的时间来实现肌肉适应, 这也可能受体液或神经因素的调节, 从而限制了他们的应用研究肌肉特定收缩诱导的适应。间接低频刺激 (10 Hz), 以诱导慢性收缩活动 (共同国家评估) 已被用作运动训练的替代模型, 因为它可以成功地导致肌肉线粒体适应在7天内, 独立于系统性因素。本文详细介绍了应用治疗大鼠骨骼肌的外科技术, 以便在今后的研究中得到广泛的应用。

我们已经表明, 慢性收缩活动 (共同国家评估) 是一种有效的工具, 以诱导良好的线粒体适应在骨骼肌肉。大鼠接受7天的共同国家评估 (每天6小时) 显示增强的线粒体生物在受激肌肉与刺激对侧 (控制) 后肢。线粒体生物的增加是由 PGC-1α蛋白表达增加 (图 3A), 被认为是线粒体生物的主调节器, 以及其他关键线粒体蛋白 cox I 和 cox IV 的升高,这是电子传输链...

Watch this Scientific Journal Video about Application of Chronic Stimulation to Study Contractile Activity-induced Rat Skeletal Muscle Phenotypic Adaptations at JoVE.com

Application of Chronic Stimulation to Study Contractile Activity-induced Rat Skeletal Muscle Phenotypic Adaptations

本议定书描述的使用慢性收缩活动模型的运动, 观察刺激诱导骨骼肌适应在大鼠后肢。

慢性刺激在收缩活动性大鼠骨骼肌表型适应性研究中的应用

Skeletal muscle is a highly adaptable tissue, as its biochemical and physiological properties are greatly altered in response to chronic exercise. To ...

application-chronic-stimulation-to-study-contractile-activity-induced

Research

JoVE Journal

Developmental Biology

6.7K 次观看.  York University. 本议定书描述的使用慢性收缩活动模型的运动, 观察刺激诱导骨骼肌适应在大鼠后肢。

视频: Application of Chronic Stimulation to Study Contractile Activity-induced Rat Skeletal Muscle Phenotypic Adaptations

Ex Vivo Culture of Pharyngeal Arches to Study Heart and Muscle Progenitors and Their Niche

The pharyngeal mesoderm of developing embryos contributes to broad regions of head and heart musculature. We have developed a novel method to study head and heart progenitor cell development with pharyngeal arches (also known as branchial arches) ex vivo. Using this method, we have recently described that the second pharyngeal arch contains self-renewing heart progenitors and serves as a microenvironment for expansion of the progenitors during mouse heart development. The progenitor cells remain undifferentiated and expansive inside the arch, but quickly become functional cardiomyocytes as they migrate out of the arch. We also reported that first pharyngeal arch contains muscle progenitors giving rise to myotubes after leaving the arch. Here, we demonstrate the procedure for the dissection and ex vivo culture of first and second pharyngeal arches from developing mouse embryos. The method enables one to study head and heart progenitor/muscle development, including cardiomyocyte and myotube formation in detail ex vivo.

Ex Vivo Culture of Pharyngeal Arches to Study Heart and Muscle Progenitors and Their Niche

Here, we present a protocol to culture pharyngeal arches to study the biology of heart and muscle progenitor cells and their microenvironment.

咽弓的体外培养研究心脏和肌肉祖细胞和自己的优势

The pharyngeal mesoderm of developing embryos contributes to broad regions of head and heart musculature. We have developed a novel method to study head ...

科研

发育生物学

Analysis of Zebrafish Larvae Skeletal Muscle Integrity with Evans Blue Dye

The zebrafish model is an emerging system for the study of neuromuscular disorders. In the study of neuromuscular diseases, the integrity of the muscle membrane is a critical disease determinant. To date, numerous neuromuscular conditions display degenerating muscle fibers with abnormal membrane integrity; this is most commonly observed in muscular dystrophies. Evans Blue Dye (EBD) is a vital, cell permeable dye that is rapidly taken into degenerating, damaged, or apoptotic cells; in contrast, it is not taken up by cells with an intact membrane. EBD injection is commonly employed to ascertain muscle integrity in mouse models of neuromuscular diseases. However, such EBD experiments require muscle dissection and/or sectioning prior to analysis. In contrast, EBD uptake in zebrafish is visualized in live, intact preparations. Here, we demonstrate a simple and straightforward methodology for performing EBD injections and analysis in live zebrafish. In addition, we demonstrate a co-injection strategy to increase efficacy of EBD analysis. Overall, this video article provides an outline to perform EBD injection and characterization in zebrafish models of neuromuscular disease.

In this study, we describe a straightforward method to perform Evans Blue Dye (EBD) analysis on zebrafish larvae. This technique is a powerful tool for the characterization of skeletal muscle integrity and delineation of zebrafish models of muscular dystrophy, and is a valuable method for the development of novel therapeutics.

斑马鱼幼虫骨骼肌诚信与伊文思蓝分析

The zebrafish model is an emerging system for the study of neuromuscular disorders.  In the study of neuromuscular diseases, the integrity of the muscle ...

Induction of Acute Skeletal Muscle Regeneration by Cardiotoxin Injection

Skeletal muscle regeneration is a physiological process that occurs in adult skeletal muscles in response to injury or disease. Acute injury-induced skeletal muscle regeneration is a widely used, powerful model system to study the events involved in muscle regeneration as well as the mechanisms and different players. Indeed, a detailed knowledge of this process is essential for a better understanding of the pathological conditions that lead to skeletal muscle degeneration, and it aids in identifying new targeted therapeutic strategies. The present work describes a detailed and reproducible protocol to induce acute skeletal muscle regeneration in mice through a single intramuscular injection of cardiotoxin (CTX). CTX belongs to the family of snake venom toxins and causes myolysis of myofibers, which eventually triggers the regeneration events. The dynamics of skeletal muscle regeneration is evaluated by histological analysis of muscle sections. The protocol also illustrates the experimental procedures for dissecting, freezing, and cutting the Tibialis Anterior muscle, as well as the routine Hematoxylin &#38; Eosin staining that is widely used for subsequent morphological and morphometric analysis.

This manuscript describes a detailed protocol to induce acute skeletal muscle regeneration in adult mice and subsequent manipulations of the muscles, such as dissection, freezing, cutting, routine staining, and myofiber cross-sectional area analysis.

通过注射心脏毒素急性骨骼肌再生的诱导

Skeletal muscle regeneration is a physiological process that occurs in adult skeletal muscles in response to injury or disease. Acute injury-induced ...

Preparation and Culture of Myogenic Precursor Cells/Primary Myoblasts from Skeletal Muscle of Adult and Aged Humans

Skeletal muscle homeostasis depends on muscle growth (hypertrophy), atrophy and regeneration. During ageing and in several diseases, muscle wasting occurs. Loss of muscle mass and function is associated with muscle fiber type atrophy, fiber type switching, defective muscle regeneration associated with dysfunction of satellite cells, muscle stem cells, and other pathophysiological processes. These changes are associated with changes in intracellular as well as local and systemic niches. In addition to most commonly used rodent models of muscle ageing, there is a need to study muscle homeostasis and wasting using human models, which due to ethical implications, consist predominantly of in vitro cultures. Despite the wide use of human Myogenic Progenitor Cells (MPCs) and primary myoblasts in myogenesis, there is limited data on using human primary myoblast and myotube cultures to study molecular mechanisms regulating different aspects of age-associated muscle wasting, aiding in the validation of mechanisms of ageing proposed in rodent muscle. The use of human MPCs, primary myoblasts and myotubes isolated from adult and aged people, provides a physiologically relevant model of molecular mechanisms of processes associated with muscle growth, atrophy and regeneration. Here we describe in detail a robust, inexpensive, reproducible and efficient protocol for the isolation and maintenance of human MPCs&#160;and their progeny&#160;&#8212; myoblasts and myotubes from human muscle samples using enzymatic digestion. Furthermore, we have determined the passage number at which primary myoblasts from adult and aged people undergo senescence in an in vitro culture. Finally, we show the ability to transfect these myoblasts and the ability to characterize their proliferative and differentiation capacity and propose their suitability for performing functional studies of molecular mechanisms of myogenesis and muscle wasting in vitro.

This protocol describes a robust, reproducible and simple method of isolation and culture of myoblast progenitor cells from the skeletal muscle of adult and aged people. The muscles used here include foot and leg muscles. This approach enables the isolation of an enriched population of primary myoblasts for functional studies.

制备及文化活动从成年和老年人类骨骼肌成肌前体细胞/成肌细胞主要的

Skeletal muscle homeostasis depends on muscle growth (hypertrophy), atrophy and regeneration. During ageing and in several diseases, muscle wasting ...

Evaluation of Injury-induced Senescence and In Vivo Reprogramming in the Skeletal Muscle

Cellular senescence is a stress response that is characterized by a stable cellular growth arrest, which is important for many physiological and pathological processes, such as cancer and ageing. Recently, senescence has also been implicated in tissue repair and regeneration. Therefore, it has become increasingly critical to identify senescent cells in vivo. Senescence-associated &#946;-galactosidase (SA-&#946;-Gal) assay is the most widely used assay to detect senescent cells both in culture and in vivo. This assay is based on the increased lysosomal contents in the senescent cells, which allows the histochemical detection of lysosomal &#946;-galactosidase activity at suboptimum pH (6 or 5.5). In comparison with other assays, such as flow cytometry, this allows the identification of senescent cells in their resident environment, which offers valuable information such as the location relating to the tissue architecture, the morphology, and the possibility of coupling with other markers via immunohistochemistry&#160;(IHC). The major limitation of the SA-&#946;-Gal assay is the requirement of fresh or frozen samples.
Here, we present a detailed protocol to understand how cellular senescence promotes cellular plasticity and tissue regeneration in vivo. We use SA-&#946;-Gal to detect senescent cells in the skeletal muscle upon injury, which is a well-established system to study tissue regeneration. Moreover, we use&#160;IHC to detect Nanog, a marker of pluripotent stem cells, in a transgenic mouse model. This protocol enables us to examine and quantify cellular senescence in the context of induced cellular plasticity and in vivo reprogramming.

Evaluation of Injury-induced Senescence and In Vivo Reprogramming in the Skeletal Muscle

Here we present a detailed protocol to detect both senescent and pluripotent stem cells in the skeletal muscle upon injury while inducing in vivo reprogramming. This method is suitable for evaluating the role of cellular senescence during tissue regeneration and reprogramming in vivo.

骨骼肌损伤诱导衰老和体内重编程的评价

Cellular senescence is a stress response that is characterized by a stable cellular growth arrest, which is important for many physiological and ...

Identification of Skeletal Muscle Satellite Cells by Immunofluorescence with Pax7 and Laminin Antibodies

Immunofluorescence is an effective method that helps to identify different cell types on tissue sections. In order to study the desired cell population, antibodies for specific cell markers are applied on tissue sections. In adult skeletal muscle, satellite cells (SCs) are stem cells that contribute to muscle repair and regeneration. Therefore, it is important to visualize and trace the satellite cell population under different physiological conditions. In resting skeletal muscle, SCs reside between the basal lamina and myofiber plasma membrane. A commonly used marker for identifying SCs on the myofibers or in cell culture is the paired box protein Pax7. In this article, an optimized Pax7 immunofluorescence protocol on skeletal muscle sections is presented that minimizes non-specific staining and background. Another antibody that recognizes a protein (laminin) of the basal lamina was also added to help identify SCs. Similar protocols can also be used to perform double or triple labeling with Pax7 and antibodies for additional proteins of interest.

The precise identification of satellite cells is essential for studying their functions under various physiological and pathological conditions. This article presents a protocol to identify satellite cells on adult skeletal muscle sections by immunofluorescence-based staining.

Pax7 和层粘连蛋白抗体免疫荧光法鉴定骨骼肌卫星细胞

Immunofluorescence is an effective method that helps to identify different cell types on tissue sections. In order to study the desired cell population, ...

In Vitro Generation of Somite Derivatives from Human Induced Pluripotent Stem Cells

In response to signals such as WNTs, bone morphogenetic proteins (BMPs), and sonic hedgehog (SHH) secreted from surrounding tissues, somites (SMs) give rise to multiple cell types, including the myotome (MYO), sclerotome (SCL), dermatome (D), and syndetome (SYN), which in turn develop into skeletal muscle, axial skeleton, dorsal dermis, and axial tendon/ligament, respectively. Therefore, the generation of SMs and their derivatives from human induced pluripotent stem cells (iPSCs) is critical to obtain pluripotent stem cells (PSCs) for application in regenerative medicine and for disease research in the field of orthopedic surgery. Although the induction protocols for MYO and SCL from PSCs have been previously reported by several researchers, no study has yet demonstrated the induction of SYN and D from iPSCs. Therefore, efficient induction of fully competent SMs remains a major challenge. Here, we recapitulate human SM patterning with human iPSCs in vitro by mimicking the signaling environment during chick/mouse SM development, and report on methods of systematic induction of SM derivatives (MYO, SCL, D, and SYN) from human iPSCs under chemically defined conditions through the presomitic mesoderm (PSM) and SM states. Knowledge regarding chick/mouse&#160;SM development was successfully applied to the induction of SMs with human iPSCs. This method could be a novel tool for studying human somitogenesis and patterning without the use of embryos and for cell-based therapy and disease modeling.

We present here a protocol for the differentiation of human induced pluripotent stem cells into each somite derivative (myotome, sclerotome, dermatome, and syndetome) in chemically defined conditions, which has applications in future disease modeling and cell-based therapies in orthopedic surgery.

人诱导多能干细胞体外生成体细胞衍生物的研究

In response to signals such as WNTs, bone morphogenetic proteins (BMPs), and sonic hedgehog (SHH) secreted from surrounding tissues, somites (SMs) give ...

X-ray Diffraction of Intact Murine Skeletal Muscle as a Tool for Studying the Structural Basis of Muscle Disease

Transgenic mouse models have been important tools for studying the relationship of genotype to phenotype for human diseases including those of skeletal muscle. Mouse skeletal muscle has been shown to produce high quality X-ray diffraction patterns on third generation synchrotron beamlines providing an opportunity to link changes at the level of the genotype to functional phenotypes in health and disease by determining the structural consequences of genetic changes. We present detailed protocols for preparation of specimens, collecting the X-ray patterns and extracting relevant structural parameters from the X-ray patterns that may help guide experimenters wishing to perform such experiments for themselves.

We present detailed protocols for performing small-angle X-ray diffraction experiments using intact mouse skeletal muscles. With the wide availability of transgenic mouse models for human diseases, this experimental platform can form a useful test bed for elucidating the structural basis of genetic muscle diseases

完整毛里丝骨骼肌的X射线衍射作为研究肌肉疾病结构基础的工具

Transgenic mouse models have been important tools for studying the relationship of genotype to phenotype for human diseases including those of skeletal ...

Isolation, Culture, Characterization, and Differentiation of Human Muscle Progenitor Cells from the Skeletal Muscle Biopsy Procedure

The use of primary human tissue and cells is ideal for the investigation of biological and physiological processes such as the skeletal muscle regenerative process. There are recognized challenges to working with human primary adult stem cells, particularly human muscle progenitor cells (hMPCs) derived from skeletal muscle biopsies, including low cell yield from collected tissue and a large degree of donor heterogeneity of growth and death parameters among cultures. While incorporating heterogeneity into experimental design requires a larger sample size to detect significant effects, it also allows us to identify mechanisms that underlie variability in hMPC&#160;expansion capacity, and thus allows us to better understand heterogeneity in skeletal muscle regeneration. Novel mechanisms that distinguish the expansion capacity of cultures have the potential to lead to the development of therapies to improve skeletal muscle regeneration.

We present techniques for isolating, culturing, characterizing, and differentiating human primary muscle progenitor cells (hMPCs) obtained from skeletal muscle biopsy tissue. hMPCs obtained and characterized through these methods can be used to subsequently address research questions related to human myogenesis and skeletal muscle regeneration.

从骨骼肌活检程序分离、培养、表征和分化人类肌肉祖细胞

The use of primary human tissue and cells is ideal for the investigation of biological and physiological processes such as the skeletal muscle ...

Performing Human Skeletal Muscle Xenografts in Immunodeficient Mice

Treatment effects observed in animal studies often fail to be recapitulated in clinical trials. While this problem is multifaceted, one reason for this failure is the use of inadequate laboratory models. It is challenging to model complex human diseases in traditional laboratory organisms, but this issue can be circumvented through the study of human xenografts. The surgical method we describe here allows for the creation of human skeletal muscle xenografts, which can be used to model muscle disease and to carry out preclinical therapeutic testing. Under an Institutional Review Board (IRB)-approved protocol, skeletal muscle specimens are acquired from patients and then transplanted into NOD-Rag1null IL2r&gamma;null (NRG) host mice. These mice are ideal hosts for transplantation studies due to their inability to make mature lymphocytes and are thus unable to develop cell-mediated and humoral adaptive immune responses. Host mice are anaesthetized with isoflurane, and the mouse tibialis anterior and extensor digitorum longus muscles are removed. A piece of human muscle is then placed in the empty tibial compartment and sutured to the proximal and distal tendons of the peroneus longus muscle. The xenografted muscle is spontaneously vascularized and innervated by the mouse host, resulting in robustly regenerated human muscle that can serve as a model for preclinical studies.

Complex human diseases can be challenging to model in traditional laboratory model systems. Here, we describe a surgical approach to model human muscle disease through the transplantation of human skeletal muscle biopsies into immunodeficient mice.

在免疫缺陷小鼠中表演人类骨骼肌异种移植物

Treatment effects observed in animal studies often fail to be recapitulated in clinical trials. While this problem is multifaceted, one reason for this ...