Buzhong Yiqi Decoction accelerates skeletal muscle regeneration

Abstract

Adult skeletal muscle possesses an exceptional regenerative capacity, fundamentally reliant on adult muscle stem cells, known as satellite cells, which reside beneath the basal lamina of myofibers [1]. In their resting state, satellite cells remain quiescent; however, they activate, proliferate, differentiate, and fuse in response to pathological stress or injury, ultimately contributing to the repair and restoration of damaged myofibers [2]. Aging and the onset of skeletal muscle degenerative diseases significantly impair this regenerative ability, leading to a marked reduction in muscle mass and strength, which culminates in progressive muscle weakness and dysfunction [3,4]. Two notable examples of such degenerative conditions are age-related sarcopenia and muscular dystrophy, both of which present considerable public health challenges due to their increasing global prevalence. Currently, these diseases lack definitive therapeutic interventions, underscoring the urgent need for innovative treatments. Restoring the regenerative capacity of skeletal muscle may offer a promising therapeutic approach to halt or even reverse the progression of these muscular degenerative disorders. Buzhong Yiqi Decoction (BYD), a traditional Chinese medicine formula known for its qi-supplementing properties, comprises several key herbs, including Huangqi (Astragalus membranaceus), Baizhu (Atractylodes atractylodes), Chenpi (Pericarpium citri reticulatae), Shengma (Rhizoma cimicifugae), Chaihu (Radix bupleuri), Rensheng (Ginseng), Gancao (Liquo rice), and Danggui (Radix Angelicae Sinensis). Clinically, BYD is utilized to treat conditions such as allergic rhinitis, gut microbiota disorders, and chronic obstructive pulmonary disease. Notably, BYD is frequently prescribed for myasthenia gravis, a condition characterized by partial or systemic skeletal muscle weakness and fatigue. Modified BYD treatments have been shown to alleviate fatigue and muscle weakness while improving the quality of life for patients with myasthenia gravis [5,6]. Numerous clinical observations indicate that combining BYD with Western medicine is more effective than Western medicine alone in managing myasthenia gravis [7,8]. A randomized controlled trial conducted by Hu et al. [9] demonstrated the efficacy of BYD in addressing cancer-related fatigue and weakness in patients with cervical carcinoma. The effectiveness of BYD in alleviating myasthenia gravis and mitigating cancer-related fatigue suggests its potential role in regulating skeletal muscle homeostasis and function. The maintenance of skeletal muscle homeostasis is primarily achieved through effective muscle regeneration in response to injury or pathological stress. However, no experimental evidence indicates whether BYD can enhance skeletal muscle regeneration. To explore the potential role of BYD in regulating skeletal muscle regeneration, we established a cardiotoxin (CTX)-induced muscle injury and regeneration model in mice. All animal procedures were approved by the Animal Ethics Committee of Peking Union Medical College (ACUC-A01-2019-012). The tibialis anterior (TA) muscle of 8-week-old male C57BL/6j mice was injured via intramuscular injection of CTX (20 μL of 10 μM), followed by daily intragastric administration of BYD (15 μL/g body weight) (Figure 1A). Mice receiving daily intragastric administration of double-distilled water (ddH2O) served as vehicle controls (Figure 1A). Muscle regeneration was assessed at 3, 5, 7 and 14 days post-injury (dpi) through hematoxylin and eosin (H&E) staining (Figure 1B) and by quantifying the size of regenerating myofibers (Figure 1C,D). The H&E-stained cross-section of the TA muscle revealed a significant infiltration of immune cells in the injured muscle at the early time point of 3 dpi (Figure 1B). Notably, we observed a reduction in immune cell presence at 5 dpi in the BYD-treated group compared to the vehicle control (Figure 1B), indicating that BYD promotes the subsidence of inflammation during acute muscle injury and regeneration. Both H&E staining and quantification data demonstrated that regenerating myofibers, characterized by centralized myonuclei, were significantly larger at 7 dpi (Figure 1B,C) and 14 dpi (Figure 1B,D) in the BYD-treated group compared to controls, suggesting that BYD accelerates skeletal muscle regeneration.

1. Introduction

Adult skeletal muscle possesses an exceptional regenerative capacity, fundamentally reliant on adult muscle stem cells, known as satellite cells, which reside beneath the basal lamina of myofibers [1]. In their resting state, satellite cells remain quiescent; however, they activate, proliferate, differentiate, and fuse in response to pathological stress or injury, ultimately contributing to the repair and restoration of damaged myofibers [2]. Aging and the onset of skeletal muscle degenerative diseases significantly impair this regenerative ability, leading to a marked reduction in muscle mass and strength, which culminates in progressive muscle weakness and dysfunction [3,4]. Two notable examples of such degenerative conditions are age-related sarcopenia and muscular dystrophy, both of which present considerable public health challenges due to their increasing global prevalence. Currently, these diseases lack definitive therapeutic interventions, underscoring the urgent need for innovative treatments. Restoring the regenerative capacity of skeletal muscle may offer a promising therapeutic approach to halt or even reverse the progression of these muscular degenerative disorders.

Buzhong Yiqi Decoction (BYD), a traditional Chinese medicine formula known for its qi-supplementing properties, comprises several key herbs, including Huangqi (Astragalus membranaceus), Baizhu (Atractylodes atractylodes), Chenpi (Pericarpium citri reticulatae), Shengma (Rhizoma cimicifugae), Chaihu (Radix bupleuri), Rensheng (Ginseng), Gancao (Liquo rice), and Danggui (Radix Angelicae Sinensis). Clinically, BYD is utilized to treat conditions such as allergic rhinitis, gut microbiota disorders, and chronic obstructive pulmonary disease. Notably, BYD is frequently prescribed for myasthenia gravis, a condition characterized by partial or systemic skeletal muscle weakness and fatigue. Modified BYD treatments have been shown to alleviate fatigue and muscle weakness while improving the quality of life for patients with myasthenia gravis [5,6]. Numerous clinical observations indicate that combining BYD with Western medicine is more effective than Western medicine alone in managing myasthenia gravis [7,8]. A randomized controlled trial conducted by Hu et al. [9] demonstrated the efficacy of BYD in addressing cancer-related fatigue and weakness in patients with cervical carcinoma.

The effectiveness of BYD in alleviating myasthenia gravis and mitigating cancer-related fatigue suggests its potential role in regulating skeletal muscle homeostasis and function. The maintenance of skeletal muscle homeostasis is primarily achieved through effective muscle regeneration in response to injury or pathological stress. However, no experimental evidence indicates whether BYD can enhance skeletal muscle regeneration.