Kim Hyunyoung, Ranjit Rojina, Claflin Dennis R, Georgescu Constantin, Wren Jonathan D, Brooks Susan V, Miller Benjamin F, Ahn Bumsoo
Department of Internal Medicine, Wake Forest University School of Medicine, Winston-Salem, North Carolina, USA.
Aging and Metabolism Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, USA.
Aging Cell. 2024 Dec;23(12):e14323. doi: 10.1111/acel.14323. Epub 2024 Sep 2.
Sarcopenia, the progressive loss of muscle mass and function, universally affects older adults and is closely associated with frailty and reduced quality of life. Despite the inevitable consequences of sarcopenia and its relevance to healthspan, no pharmacological therapies are currently available. Ghrelin is a gut-released hormone that increases appetite and body weight through acylation. Acylated ghrelin activates its receptor, growth hormone secretagogue receptor 1a (GHSR1a), in the brain by binding to it. Studies have demonstrated that acyl and unacylated ghrelin (UnAG) both have protective effects against acute pathological conditions independent of receptor activation. Here, we investigated the long-term effects of UnAG in age-associated muscle atrophy and contractile dysfunction in mice. Four-month-old and 18-month-old mice were subjected to either UnAG or control treatment for 10 months. UnAG did not affect food consumption or body weight. Gastrocnemius and quadriceps muscle weights were reduced by 20%-30% with age, which was partially protected against by UnAG. Specific force, force per cross-sectional area, measured in isolated extensor digitorum longus muscle was diminished by 30% in old mice; however, UnAG prevented the loss of specific force. UnAG also protected from decreases in mitochondrial respiration and increases in hydrogen peroxide generation of skeletal muscle of old mice. Results of bulk mRNA-seq analysis and our contractile function data show that UnAG reversed neuromuscular junction impairment that occurs with age. Collectively, our data revealed the direct role of UnAG in mitigating sarcopenia in mice, independent of food consumption or body weight, implicating UnAG treatment as a potential therapy against sarcopenia.
肌肉减少症是指肌肉质量和功能的逐渐丧失，普遍影响老年人，且与身体虚弱和生活质量下降密切相关。尽管肌肉减少症会带来不可避免的后果，且与健康寿命相关，但目前尚无药物治疗方法。胃饥饿素是一种由肠道释放的激素，通过酰化作用增加食欲和体重。酰化胃饥饿素通过与大脑中的生长激素促分泌素受体1a（GHSR1a）结合来激活该受体。研究表明，酰化和未酰化的胃饥饿素（UnAG）均具有独立于受体激活的针对急性病理状况的保护作用。在此，我们研究了UnAG对小鼠年龄相关的肌肉萎缩和收缩功能障碍的长期影响。对4个月大和18个月大的小鼠进行UnAG或对照处理，为期10个月。UnAG不影响食物摄入量或体重。随着年龄增长，腓肠肌和股四头肌的重量减少了20%-30%，而UnAG对此有部分保护作用。在离体的趾长伸肌中测量的比肌力（每横截面积的力量）在老年小鼠中降低了30%；然而，UnAG可防止比肌力的丧失。UnAG还可防止老年小鼠骨骼肌的线粒体呼吸减少和过氧化氢生成增加。大量mRNA测序分析结果和我们的收缩功能数据表明，UnAG可逆转随年龄出现的神经肌肉接头损伤。总体而言，我们的数据揭示了UnAG在减轻小鼠肌肉减少症方面具有直接作用，且独立于食物摄入量或体重，这表明UnAG治疗可能是一种对抗肌肉减少症的潜在疗法。
