CN108347987A - 将多酚用于肌肉骨骼健康的组合物和方法 - Google Patents
将多酚用于肌肉骨骼健康的组合物和方法 Download PDFInfo
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Abstract
本发明公开了一种包含一种或多种多酚诸如橄榄苦苷、芦丁、姜黄素或槲皮素的组合物,所述组合物可治疗或预防肌肉减少症、减少肌肉功能(例如肌肉力量、步行速度等)的损失、增强肌肉功能和/或改善肌肉萎缩后的肌肉功能的恢复。可将所述组合物施用给老年人和/或虚弱的个体。
Description
背景技术
本公开一般涉及使用一种或多种多酚来改善或维持肌肉骨骼健康的组合物和方法。更具体地讲,本公开涉及施用包含一种或多种多酚的组合物来治疗、预防肌肉减少症或减缓肌肉减少症的进展;减少肌肉功能(例如肌肉力量,步行速度等)的损失;增强肌肉功能,和/或改善肌肉萎缩或损伤后的肌肉功能的恢复。
肌肉损失表现在几种危及生命的疾病中,包括肌肉减少症。萎缩(损失)和肥大(增量)之间的平衡是维持骨骼肌质量的关键。然而,骨骼肌是终末分化的,因此了解允许这种可塑性的机制是长期健康和生存的中心。
肌肉减少症被定义为与年龄相关的肌肉质量和功能(包括肌肉力量和步行速度)的损失。肌肉功能和体质能力随着肌肉质量的损失而下降。通过受损的肌肉功能,可高度预测高龄时活动力丧失、残疾和死亡的发生率。随着老年人口的不断增长,肌肉减少症变得越来越普遍,有45%的美国老年人口具有中度至重度症状。美国医疗保健中归因于肌肉减少症的直接和间接成本达到了近190亿美元。因此,预防和/或治疗肌肉减少症将对我们社会的健康和生活品质,并从而对与医疗保健相关的经济产生巨大影响。不幸的是,对肌肉减少症的病因学和病理生理机制的了解仍然很少,这使得难以采取有效的预防或治疗措施。
提出用来解释随着衰老观察到的渐进性肌肉损失的主要假说之一是由于营养物质对肌肉蛋白质合成的刺激降低,导致对膳食摄入的合成代谢作用减弱。此假说被称为肌肉合成代谢抗性。此外,氧化应激和/或低度炎症也已被证明与老年人的虚弱相关,并且可以直接地或通过肌肉对胰岛素的敏感性降低而部分地导致合成代谢抗性。
发明内容
不受理论束缚,本发明人认为肌卫星细胞和成肌细胞可能是骨骼肌质量的增加/损失的中心因素,因此可能涉及肌肉萎缩疾病和衰老的潜在治疗干预。本公开旨在提供营养解决方案来增加肥大或减少萎缩并因此限制衰老期间肌肉减少症的进展、减少肌肉功能的损失、增强肌肉功能、和/或改善肌肉萎缩后的肌肉功能的恢复。
多酚具有有效的抗氧化和/或抗炎特性,并且存在于许多植物材料诸如可可、茶和诸如浆果之类的水果中。然而,就本发明人所知,没有任何关于多酚诸如橄榄苦苷或芦丁对引发肌肉肥大或限制萎缩并因此影响整体肌肉质量(维持或限制损失)的影响的已知或已公开的内容。
因此,在一般实施方案中,本发明提供一种减少个体的肌肉功能的损失、增强个体的肌肉功能、和/或改善个体在肌肉萎缩后的肌肉功能的恢复的方法。这也有助于限制或避免合成代谢抗性。该方法包括向个体施用包含多酚的组合物。
在一个实施方案中,多酚选自橄榄苦苷、芦丁、槲皮素、姜黄素以及它们的组合。
在一个实施方案中,该组合物还包含脂肪酸。该脂肪酸可以是n-3脂肪酸。
在一个实施方案中,该组合物还包含蛋白质源。该蛋白质源可包含选自乳清蛋白、酪蛋白、豌豆蛋白、大豆蛋白以及它们的组合的蛋白质。
在一个实施方案中,该组合物包含蛋白质源、芦丁和n-3脂肪酸。
在另一个实施方案中,该组合物包含蛋白质源、姜黄素和n-3脂肪酸。
在一个实施方案中,所述肌肉功能包括选自肌肉力量、步行速度以及它们的组合的特征。
在一个实施方案中,所述个体患有肌肉减少症。
在另一个实施方案中,所述个体是具有活动能力问题或患有肌无力的老年人。
在另一个实施方案中,本公开提供了包含多酚的组合物,该多酚的营养量对于以下中的至少一者是治疗有效的:(i)治疗患有肌肉减少症的个体的肌肉减少症,(ii)预防个体的肌肉减少症,(iii)减少个体的肌肉功能的损失,(iv)增强个体的肌肉功能,或(v)改善个体在肌肉萎缩后的肌肉功能的恢复。
在一个实施方案中,多酚选自橄榄苦苷、芦丁、槲皮素、姜黄素以及它们的组合。
在一个实施方案中,组合物选自食物组合物、饮食补充剂、营养组合物、营养品、在食用前用水或乳重构的粉末状营养产品、食物添加剂、药物、饮料以及它们的组合。
在另一个实施方案中,本公开提供了预防个体的肌肉减少症的方法。该方法包括向有该风险的个体施用包含多酚的组合物。
在一个实施方案中,多酚选自橄榄苦苷、芦丁、槲皮素、姜黄素以及它们的组合。
在另一个实施方案中,本发明提供了一种制备食物组合物的方法。该方法包括向另一种成分添加多酚以形成食物组合物,所添加的多酚的量在治疗可有效用于减少个体的肌肉功能的损失、增强个体的肌肉功能、和/或改善个体在肌肉萎缩后的肌肉功能的恢复。
本公开的优点是提供一种治疗个体的肌肉减少症的组合物,诸如食物产品或食物补充剂。
本公开的另一个优点是提供一种预防肌肉减少症的组合物,诸如食物产品或食物补充剂。
本公开的另一个优点是提供一种组合物,诸如食物产品或食物补充剂,相对于在食用缺乏该组合物的饮食期间将遭受的肌肉功能的损失,该组合物减少个体的肌肉功能(例如肌肉力量、步行速度等)的损失。
本公开的另一个优点是提供一种组合物,诸如食物产品或食物补充剂,相对于因食用缺乏该组合物的饮食而存在的肌肉功能(例如肌肉力量、步行速度等),该组合物增强个体的肌肉功能(例如肌肉力量、步行速度等)。
本公开的另一个优点是提供一种组合物,诸如食物产品或食物补充剂,相对于因食用缺乏该组合物的饮食而存在的肌肉功能(例如肌肉力量、步行速度等)的恢复,该组合物改善个体在肌肉萎缩后的肌肉功能(例如肌肉力量、步行速度等)的恢复。
本公开的另一个优点是有利地促进个体的肌肉减少症的减轻、预防或治疗。
本公开的另一个优点是提供营养策略来减缓个体的肌肉减少症发展,特别是减少老年人的肌肉功能(例如肌肉力量、步行速度等)的损失。
本文描述了额外的特征和优点,根据下文的具体实施方式和附图,这些特征和优点将显而易见。
附图说明
图1-13示出了来自本文所公开的实验的数据。
图1:1.0μM的橄榄苦苷(OLP)对肌酸激酶活性(CK)的影响。在含有或不含橄榄苦苷的情况下,在4天期间培养单层鼠成肌细胞(C2C12)。相对于蛋白质含量对数据进行归一化,结果表示为平均值±均值标准误。
图2:1.5μM的橄榄苦苷(OLP)对MyoD表达的影响。在含有或不含橄榄苦苷的情况下,在4天期间培养单层鼠成肌细胞(C2C12)。将数据相对于GAPDH(甘油醛-3-磷酸脱氢酶)mRNA水平进行归一化,结果表示为平均值±均值标准误。
图3:1.5μM的橄榄苦苷(OLP)对肌细胞生成素(MyoG)表达的影响。在含有或不含橄榄苦苷的情况下,在4天期间培养单层鼠成肌细胞(C2C12)。将数据相对于GAPDH(甘油醛-3-磷酸脱氢酶)mRNA水平进行归一化,结果表示为平均值±均值标准误。
图4:1.5μM的橄榄苦苷(OLP)对趋化因子(C-X-C基序)配体1(CXCL-1)表达的影响。在存在或不存在TNF-α刺激(10ng/ml)、含有或不含橄榄苦苷的情况下,在4天期间培养单层鼠成肌细胞(C2C12)。将数据相对于GAPDH(甘油醛-3-磷酸脱氢酶)mRNA水平进行归一化,结果表示为平均值±均值标准误。
图5:1.5μM的橄榄苦苷(OLP)对趋化因子(C-C基序)配体5(CCL-15)(也称为RANTES(调节激活正常T细胞表达和分泌活性因子(regulated on activation,normal T cellexpressed and secreted)))表达的影响。在存在或不存在TNF-α刺激(10ng/ml)、含有或不含橄榄苦苷的情况下,在4天期间培养单层鼠成肌细胞(C2C12)。将数据相对于GAPDH(甘油醛-3-磷酸脱氢酶)mRNA水平进行归一化,结果表示为平均值±均值标准误。
图6:1.5μM的橄榄苦苷(OLP)对含血小板结合蛋白基序的解聚蛋白样金属蛋白酶4(A disintegrin and metalloproteinase with thrombospondin motifs 4,ADAMTS-4)表达的影响。在存在或不存在TNF-α刺激(10ng/ml)、含有或不含橄榄苦苷的情况下,在4天期间培养单层鼠成肌细胞(C2C12)。将数据相对于GAPDH(甘油醛-3-磷酸脱氢酶)mRNA水平进行归一化,结果表示为平均值±均值标准误。
图7:1.5μM的橄榄苦苷(OLP)对NF-κB(核因子活化B细胞κ轻链增强子)表达的影响。在存在或不存在TNF-α刺激(10ng/ml)、含有或不含橄榄苦苷的情况下,在4天期间培养单层鼠成肌细胞(C2C12)。将数据相对于GAPDH(甘油醛-3-磷酸脱氢酶)mRNA水平进行归一化,结果表示为平均值±均值标准误。
图8:1.5μM的橄榄苦苷(OLP)对***素内过氧化物合酶2(也称为环氧合酶-2(COX-2))表达的影响。在存在或不存在TNF-α刺激(10ng/ml)、含有或不含橄榄苦苷的情况下,在4天期间培养单层鼠成肌细胞(C2C12)。将数据相对于GAPDH(甘油醛-3-磷酸脱氢酶)mRNA水平进行归一化,结果表示为平均值±均值标准误。
图9:1.5μM的橄榄苦苷(OLP)对白介素-6(IL-6)表达的影响。在存在或不存在TNF-α刺激(10ng/ml)、含有或不含橄榄苦苷的情况下,在4天期间培养单层鼠成肌细胞(C2C12)。将数据相对于GAPDH(甘油醛-3-磷酸脱氢酶)mRNA水平进行归一化,结果表示为平均值±均值标准误。
图10:1.5μM的橄榄苦苷(OLP)对Forkhead box O3(FOXO3)表达的影响。在存在或不存在TNF-α刺激(10ng/ml)、含有或不含橄榄苦苷的情况下,在4天期间培养单层鼠成肌细胞(C2C12)。将数据相对于GAPDH(甘油醛-3-磷酸脱氢酶)mRNA水平进行归一化,结果表示为平均值±均值标准误。
图11:芦丁和n-3脂肪酸(RUT+n-3 FA)对老年大鼠瘦体增量的影响。给20个月大的大鼠喂食对照饮食或补充有芦丁和n-3脂肪酸的相同饮食3个月。结果表示为平均值±均值标准误。
图12:芦丁和n-3脂肪酸(RUT+n-3 FA)对老年大鼠从基线至补充3个月的步行速度演变的影响。给20个月大的大鼠喂食对照饮食或补充有芦丁和n-3脂肪酸的相同饮食3个月。结果表示为平均值±均值标准误。
图13:芦丁和n-3脂肪酸(RUT+n-3 FA)对老年大鼠的低度炎症(α2-巨球蛋白)的影响。给20个月大的大鼠喂食对照饮食或补充有芦丁和n-3脂肪酸的相同饮食3个月。结果表示为平均值±均值标准误。
具体实施方式
所有百分数均以占组合物总重量的重量计,除非另有表示。类似地,所有比率均按重量计,除非另有表示。提及pH时,其值对应于使用标准设备在25℃下测量的pH。如本文所用,“约”、“大约”和“基本上”应理解为是指某一数值范围内的数字,例如该所提及数字的-10%至+10%的范围内,优选该所提及数字的-5%至+5%以内,更优选该所提及数字的-1%至+1%以内,最优选该所提及数字的-0.1%至+0.1%以内。
此外,本文中的所有数值范围都应理解为包含该范围内的所有整数或分数。另外,这些数值范围应理解为对涉及该范围内任何数值或数值子集的权利要求提供支持。例如,1至10的公开应理解为支持1至8、3至7、1至9、3.6至4.6、3.5至9.9等的范围。
如本文及所附权利要求所用,除非上下文另外明确规定,否则词语的单数形式包括复数。因此,提及“一个”、“一种”和“该”通常包括相应术语的复数形式。例如,提及“一种成分”或“一种方法”包括提及多种此类成分或方法。在“X和/或Y”语境中使用的术语“和/或”应解释为“X”或“Y”,或者“X和Y”。
与此类似,词语“包括/包含/含有(comprise)”、“包括/包含/含有(comprises)”和“包括/包含/含有(comprising)”都用于包含性而非排他性地解释。同样地,术语“包括/包含(include)”、“包括/包含(including)”和“或”都应当视为包含性的,除非上下文明确禁止这一解释。然而,本公开提供的实施方案可能不含本文未明确公开的任何要素。因此,使用术语“包括/包含/含有”限定的一个实施方案的公开内容,也是“基本上由所公开的组分组成”和“由所公开的组分组成”的多个实施方案的公开内容。本文使用的术语“示例”(尤其后跟一列术语时),仅用于举例说明,而不应当被视为排他性的或全面的。本文所公开的任何实施方案可与本文所公开的任何其他实施方案结合,除非另有明确指示。
“动物”包括但不限于哺乳动物,所述哺乳动物包括但不限于啮齿动物,水栖哺乳动物,诸如狗和猫之类的家畜,诸如羊、猪、牛和马之类的农畜,以及人类。在使用“动物”、“哺乳动物”或其复数形式时,这些术语还适用于能够具有通过段落上下文表现出的或意欲表现出的作用的任何动物。如本文所用,术语“患者”应被理解为包括接受或意欲接受本文所定义的治疗的动物,尤其是哺乳动物,并且更尤其是人。虽然本文中常用术语“个体”和“患者”来指人,但本公开并非限制于此。因此,术语“个体”和“患者”是指可受益于治疗的任何动物、哺乳动物或人。
术语“老年人”是指年龄大于60岁、优选大于63岁、更优选大于65岁的人。术语“虚弱”是指身体弱(即不强壮而是脆弱)的人。
术语“治疗(treatment/treating)”包括导致病症或障碍改善,例如减轻、减少、调节或消除病症或障碍的任何效果。该术语不一定表示个体被治疗直至完全恢复。“治疗”病症或障碍的非限制性示例包括:(1)抑制病症或障碍,即阻止病症或障碍或其临床症状的发展,以及(2)缓解病症或障碍,即,使病症或障碍或其临床症状暂时或永久地消退。治疗可与患者或医生相关。
术语“预防(prevention/preventing)”是指使得所提及的病症或障碍的临床症状不在可能暴露于或易患上该病症或障碍但尚未经历或表现出该病症或障碍的症状的个体中发展。术语“病症”和“障碍”意指任何疾病、病症、症状或适应症。
相对术语“改善”、“增加”、“增强”等是指(本文所公开的)包含一种或多种多酚的组合物相对于缺乏多酚但在其它方面相同的组合物的作用。
术语“食物”、“食物产品”和“食物组合物”意指旨在供个体(例如,人类)摄入并且向个体提供至少一种营养物质的产品或组合物。本公开(包括本文所述的多个实施方案)的组合物可包含下列要素、由或基本上由下列要素组成:本文所述的基本要素和限制,以及本文所述的或者说可用于饮食中的任何其他或可选的成分、组分或限制。
如本文所用,“完全营养”包含种类全面、含量充足的常量营养素(蛋白质、脂肪和碳水化合物)和微量营养素,其对于施用该组合物的动物而言足以作为唯一营养源。从这类完全营养组合物中,个体可得到其100%的营养需求。
“多酚”是包含带有一个或多个羟基取代基的芳族环的化合物,包括功能衍生物。含有多酚的抗氧化剂包括富含多酚的植物、藻类或真菌提取物或级分,多酚包括黄酮类(异黄酮、花青素苷、原花青素和花青素、黄烷、黄酮醇、黄酮和黄烷酮)。生物类黄酮的具体示例为儿茶素类(儿茶素、表儿茶素、没食子儿茶素、表没食子儿茶素、表儿茶素没食子酸酯、表没食子儿茶素没食子酸酯)、橄榄苦苷、槲皮素、芦丁、橘皮苷、姜黄素和染料木黄酮。
本公开的一个方面是包含一种或多种多酚的组合物,该组合物用于治疗或预防个体诸如哺乳动物例如人的肌肉减少症、用于减少个体诸如哺乳动物例如人的肌肉功能(例如肌肉力量、步行速度等)的损失、用于增强个体诸如哺乳动物例如人的肌肉功能(例如肌肉力量、步行速度等)、和/或用于改善个体诸如哺乳动物例如人在肌肉萎缩后的肌肉功能(例如肌肉力量、步行速度等)的恢复。本公开的另一方面是一种方法,该方法包括向个体施用治疗有效量的包含一种或多种多酚的组合物来治疗个体的肌肉减少症、预防个体的肌肉减少症、减少个体的肌肉功能(例如肌肉力量、步行速度等)的损失、增强个体的肌肉功能(例如肌肉力量、步行速度等)、和/或改善个体在肌肉萎缩后的肌肉功能(例如肌肉力量、步行速度等)的恢复。在一个实施方案中,该组合物包含总浓度为约1μM的一种或多种多酚。
如根据本公开所治疗或预防的肌肉萎缩可由许多原因引起。例如,其可能因缺乏体力活动引起,诸如因与衰老相关的活动力丧失或低体力活动(与衰老过程相关的肌肉减少症)、髋部骨折恢复、或疾病的若干种共病(诸如癌症、AIDS、充血性心力衰竭、COPD(慢性阻塞性肺疾病)、肾衰竭、创伤、败血症和严重烧伤)。肌肉萎缩也可能因不足或不适当的营养或者饥饿而导致。非常普遍地,肌肉萎缩是由于不使用相应肌肉或相应肌肉的使用不足而导致。
本公开中所提及的肌肉优选为骨骼肌。例如,本文所公开的组合物可用于减少个体的手臂和/或腿的肌肉功能的损失。所述肌肉可以是下列中的一种或多种:腓肠肌、胫骨肌、比目鱼肌、趾长伸肌(EDL)、股二头肌、半腱肌、半膜肌或臀大肌。
肌肉萎缩可导致肌肉减少症,即由于衰老而损失肌肉质量、大小和功能。肌肉萎缩可具有不同的级别,诸如当老年人极度虚弱时的严重肌肉萎缩。极度虚弱的老年人在日常活动和照顾自己方面可能有困难。程度不太严重的肌肉萎缩将允许某些运动和某些肌肉活动,但是这些肌肉活动不足以维持完整的肌肉组织。与年龄相关的肌肉减少症的治疗或预防中所涉及的机制不同于治疗或预防年轻人的肌肉功能的损失。
本文所公开的组合物包含一种或多种多酚,并且相对于缺乏这种组合物的饮食,其可减少施用该组合物的个体的肌肉功能的损失和/或改善施用该组合物的个体的肌肉功能。在一个优选的实施方案中,所述一种或多种多酚是食品级多酚。如果化合物被普遍接受并被认为对食品应用是安全的,则该化合物被认为是“食品级”的。
可使用多酚的混合物,诸如两种或更多种多酚。多酚还可以作为富含多酚的食物组合物或其提取物提供。富含或富集多酚的植物提取物特别适用于本发明。
可可、咖啡和茶富含多酚。水果提取物或干果可以用作多酚的来源,例如梨、苹果、葡萄、酸果蔓、蓝莓、黑莓、树莓、草莓、黑醋栗、樱桃、李子和/或石榴。还有一些坚果和籽粒富含多酚,诸如栗子、榛子和亚麻籽。多酚含量高的蔬菜的非限制性示例是卷心菜、西兰花、甜菜根、朝鲜蓟头、黑橄榄、黑豆、芹菜、洋葱、欧芹和菠菜。
所述一种或多种多酚可以是纯化的化合物或部分纯化的化合物。合适的多酚的非限制性示例是酚酸;黄酮类,诸如黄酮醇、黄酮、异黄酮、黄烷酮、花青素和黄烷醇;芪类;以及木脂素类。在一个实施方案中,所述一种或多种多酚包含黄酮醇和/或黄酮醇糖苷。作为非限制性示例,所述一种或多种多酚可包含橄榄苦苷、芦丁、姜黄素或槲皮素中的一种或多种。
所述一种或多种多酚每一者可以每份0.01mg至约1g、优选0.1mg至1g、甚至更优选1mg至约1g的量存在。
实现治疗效果所需的根据本发明的组合物的有效量当然将随着特定组合物、施用途径、接受者的年龄和状况以及受治的特定障碍或疾病而变化。
举例来说,RTD(即饮型饮料)每份将含有0.01mg至500mg的每种活性成分,更优选每份约250mg。
除了所述一种或多种多酚之外,该组合物可还包含来自动物或植物起源的蛋白质源,例如乳蛋白、大豆蛋白和/或豌豆蛋白。在一个优选实施方案中,所述蛋白质源选自乳清蛋白;酪蛋白;豌豆蛋白;大豆蛋白;小麦蛋白;玉米蛋白;水稻蛋白;来自豆类、谷类食物和谷物的蛋白质;以及它们的组合。除此之外或另选地,所述蛋白质源可包含来自坚果和/或籽粒的蛋白质。
蛋白质源可包含乳清蛋白。乳清蛋白可以是未水解的或水解的乳清蛋白。乳清蛋白可以是任何乳清蛋白,例如乳清蛋白可以选自乳清蛋白浓缩物、乳清蛋白分离物、乳清蛋白胶束、乳清蛋白水解物、酸乳清、甜乳清、改性甜乳清(其中已去除酪蛋白-糖巨肽的甜乳清)、乳清蛋白的级分以及它们的任何组合。在一个优选实施方案中,所述乳清蛋白包括乳清蛋白分离物和/或改性甜乳清。
如上所述,所述蛋白质源可以来自于动物或植物来源,例如乳蛋白、大豆蛋白和/或豌豆蛋白。在一个实施方案中,所述蛋白质源包含酪蛋白。酪蛋白可以从任何哺乳动物获得,但优选地从牛乳获得,并且优选地为胶束酪蛋白。
在本发明的一个实施方案中,该组合物包含的蛋白质的量使得蛋白质(优选乳清)的摄入量为每天5g至50g蛋白质,诸如每天12g至40g蛋白质,优选15g至30g蛋白质,诸如每天16g至25克蛋白质,甚至更优选每天20克蛋白质。
所述组合物可包含一种或多种支链氨基酸。例如,所述组合物可包含亮氨酸、异亮氨酸和/或缬氨酸。所述组合物中的蛋白质源可包括游离形式的亮氨酸和/或结合成肽和/或蛋白质的亮氨酸(诸如乳制品、动物或植物蛋白)。在一个实施方案中,所述组合物包含其量最多达组合物干物质的10重量%的亮氨酸。亮氨酸可以D-亮氨酸或L-亮氨酸形式存在,优选地为L-亮氨酸形式。如果所述组合物包含亮氨酸,则该组合物可以每千克体重提供0.01g至0.04g亮氨酸、优选地每千克体重提供0.02g至0.035g亮氨酸的日剂量施用。这样的剂量特别适用于完全营养组合物,但是普通技术人员将容易地认识到如何针对口服营养补充剂(ONS)调整这些剂量。
在一个实施方案中,包含一种或多种多酚的组合物还包含脂肪酸。该脂肪酸可以是任何脂肪酸,并且可以是一种或多种脂肪酸,诸如脂肪酸的组合。该脂肪酸优选包括必需脂肪酸,诸如必需的多不饱和脂肪酸,即亚油酸(C18:2n-3)和α-亚麻酸(C18:3n-3)。该脂肪酸可包括长链多不饱和脂肪酸,诸如二十碳五烯酸(C20:5n-3)、花生四烯酸(C20:4n-6)、二十二碳六烯酸(C22:6n-3)或它们的任何组合。在一个优选实施方案中,该脂肪酸包括n-3(ω-3)脂肪酸和/或n-6(ω-6)脂肪酸。该脂肪酸优选包括二十碳五烯酸。
该脂肪酸可以来源于任何合适的含有脂肪酸的来源,诸如椰子油、菜籽油、大豆油、玉米油、红花油、棕榈油、葵花油或蛋黄。该脂肪酸的来源优选为鱼油。
基于总脂质含量计,根据本发明的n-3脂肪酸通常为至少10重量%,优选至少15重量%。在一个优选的实施方案中,日用量为每天500mg至2.5g,优选1g至1.5g n-3脂肪酸。
除了所述一种或多种多酚之外,该组合物中还可使用另一种抗炎化合物或抗氧化剂。例如,可以提供额外的抗氧化剂,该额外的抗氧化剂作为富含抗氧化剂的食物组合物或作为其提取物。“富含抗氧化剂”的食物组合物具有每100g组合物至少100的ORAC(氧自由基吸收能力)评分。
在最优选的实施方案中,该组合物至少包含蛋白质源、芦丁和n-3脂肪酸。蛋白质源优选包含乳清。
在另一个优选的实施方案中,该组合物至少包含蛋白质源、姜黄素和n-3脂肪酸。蛋白质源优选包含乳清。在更优选的实施方案中,施用该组合物以提供约20g乳清、500毫克多酚(例如姜黄素或芦丁)、1500毫克n-3脂肪酸的每日量。
在一个实施方案中,该组合物还包含维生素D。根据本发明的组合物可以例如以每份800IU至1200IU的量包含维生素D。
可将包含一种或多种多酚的组合物以治疗有效剂量施用给个体诸如人,例如老年人。该治疗有效剂量可以由本领域的技术人员确定,并且将取决于本领域的技术人员已知的许多因素,诸如病症的严重程度和个体的体重以及一般状况。
可在个体尚未发展出肌肉减少症的症状的情况下,将所述组合物以足以预防或至少部分地降低发展肌肉减少症的风险的量施用给该个体。这样的量被定义为“预防有效剂量”。同样,确切量取决于与该个体相关的多种因素,诸如他们的体重、健康状况和肌肉功能(例如肌肉力量、步行速度等)损失的程度。
该组合物优选作为个体饮食的补充剂每天施用或每周至少两次施用。在一个实施方案中,将该组合物连续多天施用给个体,优选直至相对于施用前的肌肉功能实现肌肉功能(例如肌肉力量、步行速度等)的增强。例如,可将该组合物在至少连续30天、60天或90天内每日施用给个体。又如,可将该组合物在更长时间内施用给个体,诸如1年、2年、3年、4年、5年、6年、7年、8年、9年或10年。
在一个优选实施方案中,将所述组合物施用给个体至少3个月,例如3个月至1年,并且优选至少6个月的时间。
上述施用示例不需要无中断的连续每日施用。相反,在施用中可以存在一些短暂的中断,例如在施用期间中断两至四天。施用组合物的理想持续时间可以由本领域的技术人员确定。
在一个优选实施方案中,将该组合物以口服方式或经胃肠内(例如管饲)施用给个体。例如,该组合物可以饮料、胶囊、片剂、粉末或混悬剂形式施用给个体。
该组合物可以是适合人类和/或动物食用的任何种类的组合物。例如,所述组合物可选自食物组合物、饮食补充剂、营养组合物、营养品、在食用前用水或乳重构的粉末状营养产品、食物添加剂、药物、饮料和饮品。在一个实施方案中,所述组合物是口服营养补充剂(ONS)、完全营养配方、医药、医疗产品或食物产品。在一个优选的实施方案中,该组合物以饮料形式施用给个体。所述组合物可以粉末形式储存在小袋中,然后混悬在液体如水中以供使用。
在不能或不建议口服或经胃肠内施用的一些情况下,所述组合物也可以肠胃外方式施用。
在一些实施方案中,该组合物以单一剂型施用给个体,即所有化合物均存在于一种产品中,该产品将与膳食组合提供给个体。在其它实施方案中,该组合物以分开的剂型共同施用,例如一种或多种多酚与组合物的其它组分分开施用,和/或一种或多种多酚的一部分与一种或多种多酚的另一部分分开施用。
实施例
以下非限制性示例提供了科学数据以用于发展和支持以下概念:施用包含一种或多种多酚的组合物来在施用了该组合物的个体中治疗肌肉减少症、预防肌肉减少症、减少肌肉功能(例如肌肉力量、步行速度等)的损失、增强肌肉功能(例如肌肉力量、步行速度等)、和/或改善肌肉功能(例如肌肉力量、步行速度等)的恢复。
鼠C2C12成肌细胞系(来自大腿肌肉的卫星细胞)可很好地表现肌肉萎缩和肥大。C2C12细胞在多核肌管中分化。通过测量C2C12细胞中的肌酸激酶(CK)活性来以生化方式观察成肌细胞分化及随后的肌管形成。
实验1:在本发明人所使用的模型中,用两种多酚:橄榄苦苷(来自橄榄叶)和槲皮素(芦丁的糖苷配基形式)处理C2C12细胞。肿瘤坏死因子-α(TNF-α)是一种多效细胞因子,充当许多状态下的肌肉萎缩和衰老的介质,被用作肌肉萎缩的对照。多酚处理在存在或不存在TNF-α的情况下进行。此外,将***-1(IGF-1)用作肥大的对照(图1)。
结果显示,在1μM时,橄榄苦苷能够增加肌管分化(肥大)。
实验2:在本发明人所使用的模型中,在存在或不存在TNF-α(10ng/ml)的情况下用橄榄苦苷(1.5μM)处理C2C12成肌细胞4天。TNF-α(肿瘤坏死因子-α)是一种多效细胞因子,充当许多状态下的肌肉萎缩和衰老的介质,被用作肌肉萎缩的对照。也将TNF-α用于诱导C2C12的炎性条件。在第3天和第4天,在非炎性条件下,橄榄苦苷增加了肌管分化标志物肌细胞生成素D(MyoD)(图2)和MyoG(图3),从而表明刺激肌肉肥大。在炎性条件下(具有TNF-α),在第4天橄榄苦苷降低了特异性的肌肉炎性细胞因子C-X-C基序配体1(CXCL-1)(图4)和C-C基序配体5(CCL-5)(图5)的表达,从而表明肌细胞的炎性应答降低。降低了其它非肌肉特异性的炎性细胞因子(核因子活化B细胞κ轻链增强子-NFK-B(图7)、环氧合酶-2-Cox-2(图8)和白介素-6-IL-6(图9)),从而显示橄榄苦苷的抗炎特性。最后,含血小板结合蛋白基序的解聚蛋白样金属蛋白酶4(ADAMTS-4)(图6)也被橄榄苦苷降低。在我们的模型中通过测量Forkhead box O3(FOXO3)(图10)来评价肌蛋白分解,在第3和4天橄榄苦苷降低了肌蛋白分解。
图1示出了1.0μM橄榄苦苷(OLP)对肌酸激酶活性(CK)的影响。在含有或不含橄榄苦苷的情况下,在4天期间培养单层鼠成肌细胞(C2C12)。相对于蛋白质含量对数据进行归一化,结果表示为平均值±均值标准误。基线:用分化生长培养基喂养的未分化细胞的基础对照。对照:具有分化培养基(DM)(2%马血清、1%青霉素链霉素、DMEM高葡萄糖)的基础对照。TNFa 10ng/ml:DM中含浓度为10ng/ml的肿瘤坏死因子α(萎缩的对照)。IGF-110nM:DM中含浓度为10nM的***1(肥大的对照)。OLP 1μM:DM中含浓度为1.0μM的橄榄苦苷。
图2示出了1.5μM的橄榄苦苷(OLP)对MyoD表达的影响。在含有或不含橄榄苦苷的情况下,在4天期间培养单层鼠成肌细胞(C2C12)。将数据相对于GAPDH(甘油醛-3-磷酸脱氢酶)mRNA水平进行归一化,结果表示为平均值±均值标准误。DM:具有分化培养基(2%马血清、1%青霉素链霉素、DMEM高葡萄糖)的基础对照。OLP 1.5μM:DM中含浓度为1.5μM的橄榄苦苷。
图3示出了1.5μM的橄榄苦苷(OLP)对肌细胞生成素(MyoG)表达的影响。在含有或不含橄榄苦苷的情况下,在4天期间培养单层鼠成肌细胞(C2C12)。将数据相对于GAPDH(甘油醛-3-磷酸脱氢酶)mRNA水平进行归一化,结果表示为平均值±均值标准误。DM:具有分化培养基(2%马血清、1%青霉素链霉素、DMEM高葡萄糖)的基础对照。OLP 1.5μM:DM中含浓度为1.5μM的橄榄苦苷。
图4示出了1.5μM的橄榄苦苷(OLP)对趋化因子(C-X-C基序)配体1(CXCL-1)表达的影响。在存在或不存在TNF-α刺激(10ng/ml)、含有或不含橄榄苦苷的情况下,在4天期间培养单层鼠成肌细胞(C2C12)。将数据相对于GAPDH(甘油醛-3-磷酸脱氢酶)mRNA水平进行归一化,结果表示为平均值±均值标准误。DM:具有分化培养基(2%马血清、1%青霉素链霉素、DMEM高葡萄糖)的基础对照。TNFa 10ng/ml:DM中含浓度为10ng/ml的肿瘤坏死因子α。OLP 1.5μM:DM中含浓度为1.5μM的橄榄苦苷。TNFa 10ng/ml+OLP 1.5μMM:DM中含浓度为10ng/ml的肿瘤坏死因子α和浓度为1.5μM的橄榄苦苷。
图5示出了1.5μM的橄榄苦苷(OLP)对趋化因子(C-C基序)配体5(CCL-15)(也称为RANTES(调节激活正常T细胞表达和分泌活性因子))表达的影响。在存在或不存在TNF-α刺激(10ng/ml)、含有或不含橄榄苦苷的情况下,在4天期间培养单层鼠成肌细胞(C2C12)。将数据相对于GAPDH(甘油醛-3-磷酸脱氢酶)mRNA水平进行归一化,结果表示为平均值±均值标准误。DM:具有分化培养基(2%马血清、1%青霉素链霉素、DMEM高葡萄糖)的基础对照。TNFa 10ng/ml:DM中含浓度为10ng/ml的肿瘤坏死因子α。OLP 1.5μM:DM中含浓度为1.5μM的橄榄苦苷。TNFa 10ng/ml+OLP 1.5μMM:DM中含浓度为10ng/ml的肿瘤坏死因子α和浓度为1.5μM的橄榄苦苷。
图6示出了1.5μM的橄榄苦苷(OLP)对含血小板结合蛋白基序的解聚蛋白样金属蛋白酶4(ADAMTS-4)表达的影响。在存在或不存在TNF-α刺激(10ng/ml)、含有或不含橄榄苦苷的情况下,在4天期间培养单层鼠成肌细胞(C2C12)。将数据相对于GAPDH(甘油醛-3-磷酸脱氢酶)mRNA水平进行归一化,结果表示为平均值±均值标准误。
DM:具有分化培养基(2%马血清、1%青霉素链霉素、DMEM高葡萄糖)的基础对照。TNFa 10ng/ml:DM中含浓度为10ng/ml的肿瘤坏死因子α。OLP 1.5μM:DM中含浓度为1.5μM的橄榄苦苷。TNFa 10ng/ml+OLP 1.5μMM:DM中含浓度为10ng/ml的肿瘤坏死因子α和浓度为1.5μM的橄榄苦苷。
图7示出了1.5μM的橄榄苦苷(OLP)对NF-κB(核因子活化B细胞κ轻链增强子)表达的影响。在存在或不存在TNF-α刺激(10ng/ml)、含有或不含橄榄苦苷的情况下,在4天期间培养单层鼠成肌细胞(C2C12)。将数据相对于GAPDH(甘油醛-3-磷酸脱氢酶)mRNA水平进行归一化,结果表示为平均值±均值标准误。DM:具有分化培养基(2%马血清、1%青霉素链霉素、DMEM高葡萄糖)的基础对照。TNFa 10ng/ml:DM中含浓度为10ng/ml的肿瘤坏死因子α。OLP 1.5μM:DM中含浓度为1.5μM的橄榄苦苷。TNFa 10ng/ml+OLP 1.5μMM:DM中含浓度为10ng/ml的肿瘤坏死因子α和浓度为1.5μM的橄榄苦苷。
图8示出了1.5μM的橄榄苦苷(OLP)对***素内过氧化物合酶2(也称为环氧合酶-2(COX-2))表达的影响。在存在或不存在TNF-α刺激(10ng/ml)、含有或不含橄榄苦苷的情况下,在4天期间培养单层鼠成肌细胞(C2C12)。将数据相对于GAPDH(甘油醛-3-磷酸脱氢酶)mRNA水平进行归一化,结果表示为平均值±均值标准误。DM:具有分化培养基(2%马血清、1%青霉素链霉素、DMEM高葡萄糖)的基础对照。TNFa 10ng/ml:DM中含浓度为10ng/ml的肿瘤坏死因子α。OLP 1.5μM:DM中含浓度为1.5μM的橄榄苦苷。TNFa 10ng/ml+OLP 1.5μMM:DM中含浓度为10ng/ml的肿瘤坏死因子α和浓度为1.5μM的橄榄苦苷。
图9示出了1.5μM的橄榄苦苷(OLP)对白介素-6(IL-6)表达的影响。在存在或不存在TNF-α刺激(10ng/ml)、含有或不含橄榄苦苷的情况下,在4天期间培养单层鼠成肌细胞(C2C12)。将数据相对于GAPDH(甘油醛-3-磷酸脱氢酶)mRNA水平进行归一化,结果表示为平均值±均值标准误。DM:具有分化培养基(2%马血清、1%青霉素链霉素、DMEM高葡萄糖)的基础对照。TNFa 10ng/ml:DM中含浓度为10ng/ml的肿瘤坏死因子α。OLP 1.5μM:DM中含浓度为1.5μM的橄榄苦苷。TNFα10ng/ml+OLP 1.5μM:DM中含浓度为10ng/ml的肿瘤坏死因子α和浓度为1.5μM的橄榄苦苷。
图10示出了1.5μM的橄榄苦苷(OLP)对Forkhead box O3(FOXO3)表达的影响。在存在或不存在TNF-α刺激(10ng/ml)、含有或不含橄榄苦苷的情况下,在4天期间培养单层鼠成肌细胞(C2C12)。将数据相对于GAPDH(甘油醛-3-磷酸脱氢酶)mRNA水平进行归一化,结果表示为平均值±均值标准误。DM:具有分化培养基(2%马血清、1%青霉素链霉素、DMEM高葡萄糖)的基础对照。TNFα10ng/ml:DM中含浓度为10ng/ml的肿瘤坏死因子α。OLP 1.5μM:DM中含浓度为1.5μM的橄榄苦苷。TNFα10ng/ml+OLP 1.5μM:DM中含浓度为10ng/ml的肿瘤坏死因子α和浓度为1.5μM的橄榄苦苷。
综观来说,这些结果表明,橄榄苦苷通过炎性途径抵消炎症的作用以限制蛋白质降解并刺激肌肉肥大。
实验3:老年大鼠是评估营养干预在年龄相关性肌肉衰退中的效果的良好模型。通过这个模型,可以观察到,与人体一样,肌肉质量和功能随着年龄增长而下降。在本发明人所使用的该模型中,20个月大的大鼠用正常饮食或用补充有一种多酚(芦丁)和n-3脂肪酸(n-3 FA)的相同饮食喂养3个月。与对照组相比,芦丁+n-3 FA组的通过核磁共振(NMR)测量的瘦体增量显著更高。所观察到的步行速度(活动能力的参数)随年龄增加的下降,通过补充芦丁+n-3 FA而显著降低。通过测量α2-巨球蛋白的循环浓度来评价低度炎症,并且芦丁和n-3 FA降低了低度炎症。(图11-图13)
图11显示了芦丁和n-3脂肪酸(RUT+n-3 FA)对老年大鼠瘦体增量的影响。给20个月大的大鼠喂食对照饮食或补充有芦丁和n-3 FA的相同饮食3个月。结果表示为平均值±均值标准误CTL:对照饮食。RUT+n-3 FA:含芦丁和n-3脂肪酸的对照饮食。
然后,图12显示了芦丁和n-3脂肪酸(RUT+n-3 FA)对老年大鼠从基线至补充3个月的步行速度演变的影响。给20个月大的大鼠喂食对照饮食或补充有芦丁和n-3 FA的相同饮食3个月。结果表示为平均值±均值标准误CTL:对照饮食。RUT+n-3 FA:含芦丁和n-3脂肪酸的对照饮食。
另外,图13显示了老年大鼠中芦丁和n-3脂肪酸(RUT+n-3 FA)对低度炎症(α2-巨球蛋白)的影响。给20个月大的大鼠喂食对照饮食或补充有芦丁和n-3 FA的相同饮食3个月。结果表示为平均值±均值标准误CTL:对照饮食。RUT+n-3 FA:含芦丁和n-3脂肪酸的对照饮食
综观来说,这些结果表明,补充芦丁和n-3 FA减少了老年大鼠的肌肉质量的损失并改善了老年大鼠的肌肉功能。这与低度炎症减少相关。
Claims (19)
1.一种减少个体的肌肉功能的损失、增强个体的肌肉功能和/或改善个体在肌肉萎缩后的肌肉功能的恢复的方法,所述方法包括向所述个体施用包含多酚的组合物。
2.根据权利要求1所述的方法,其中所述多酚选自橄榄苦苷、芦丁、槲皮素、姜黄素以及它们的组合。
3.根据权利要求1所述的方法,其中所述组合物包含脂肪酸。
4.根据权利要求3所述的方法,其中所述脂肪酸是n-3脂肪酸。
5.根据权利要求1所述的方法,其中所述组合物包含蛋白质源。
6.根据权利要求5所述的方法,其中所述蛋白质源包含选自乳清蛋白、酪蛋白、豌豆蛋白、大豆蛋白以及它们的组合的蛋白质。
7.根据权利要求1所述的方法,其中所述组合物包含蛋白质源,优选乳清蛋白;芦丁和n-3脂肪酸。
8.根据权利要求1所述的方法,其中所述组合物包含蛋白质源,优选乳清蛋白;姜黄素和n-3脂肪酸。
9.根据权利要求1所述的方法,其中所述肌肉功能包括选自肌肉力量、步行速度以及它们的组合的特征。
10.根据权利要求1所述的方法,其中所述个体患有肌肉减少症或者是活动能力有问题或患有肌无力的老年人。
11.一种组合物,所述组合物包含多酚,所述多酚的量对于以下中的至少一者是治疗有效的:(i)治疗患有肌肉减少症的个体的肌肉减少症,(ii)预防个体的肌肉减少症,(iii)减少个体的肌肉功能的损失,(iv)增强个体的肌肉功能,或(v)改善个体在肌肉萎缩或损伤后的肌肉功能的恢复。
12.根据权利要求11所述的组合物,其中所述多酚选自橄榄苦苷、芦丁、槲皮素、姜黄素以及它们的组合。
13.根据权利要求11所述的组合物,其中所述组合物选自食物组合物、饮食补充剂、营养组合物、营养品、在食用前用水或乳重构的粉末状营养产品、食物添加剂、药物、饮料以及它们的组合。
14.根据权利要求11所述的组合物,其中所述多酚选自橄榄苦苷、芦丁、槲皮素、姜黄素以及它们的组合。
15.根据权利要求11所述的组合物,其中所述组合物包含脂肪酸,优选n-3脂肪酸。
16.根据权利要求11所述的组合物,其中所述组合物包含选自乳清蛋白、酪蛋白、豌豆蛋白、大豆蛋白以及它们的组合的蛋白质源。
17.根据权利要求11所述的组合物,其中所述组合物包含蛋白质源、芦丁和n-3脂肪酸。
18.根据权利要求11所述的组合物,其中所述组合物包含蛋白质源、姜黄素和n-3脂肪酸。
19.根据权利要求17和18所述的组合物,其中所述蛋白质源包含乳清蛋白。
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