Evidence-Based Complementary and Alternative Medicine
Volume 2018 (2018), Article ID 8654719, 27 pages
https://doi.org/10.1155/2018/8654719

Review Article

A Review of Complementary and Alternative Medicine Therapies on Muscular Atrophy: A Literature Review of In Vivo/In Vitro Studies

Seong-Mok Jeong, Byung-Kwan Seo, Yeon-Cheol Park, and Yong-Hyeon Baek

Department of Acupuncture & Moxibustion, Kyung Hee University Hospital at Gangdong, 149 Sangil-dong, Gangdong-gu, Seoul 134-727, Republic of Korea

Correspondence should be addressed to Yong-Hyeon Baek; byhacu@khu.ac.kr

Seong-Mok Jeong and Byung-Kwan Seo contributed equally to this work.

Received 13 July 2018; Revised 28 August 2018; Accepted 22 October 2018; Published 18 November 2018

Academic Editor: Mariangela Rondanelli

Copyright © 2018 Seong-Mok Jeong et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract.

Objective. The objective of this review is to evaluate the recent treatment and study trends of complementary and alternative medicine (CAM) treatments on muscular atrophy by reviewing in vivo/in vitro studies. Materials and Methods. The searches were conducted via electronic databases including PubMed, the Cochrane Library, China National Knowledge Infrastructure (CNKI), Wanfang MED, and five Korean databases. Only in vivo and in vitro studies were included in this study. Results. A total of 44 studies (27 in vivo studies, 8 in vitro studies, and 9 in vivo with in vitro) were included. No serious maternal or fetal complications occurred. There were various animal models induced with muscular atrophy through “hindlimb suspension”, “nerve damage”, ‘alcohol or dexamethasone treatment’, “diabetes”, “CKD”, “stroke”, “cancer”, “genetic modification”, etc. In 28 of 36 articles measuring muscle mass, CAM significantly increased the mass. Additionally, 10 of them showed significant improvement in muscle function. In most in vitro studies, significant increases in both the diameter of myotubes and muscle cell numbers were reported. The mechanisms of action of protein synthesis, degradation, autophagy, and apoptotic markers were also investigated. Conclusions. These results demonstrate that CAM could prevent muscular atrophy. Further studies about CAM on muscular atrophy are needed.

1. Introduction

Muscle atrophy is defined as a reduction in muscle mass, which is a concept that covers partial or complete wasting away from muscle. In general, functional and morphological changes caused by muscular atrophy usually result in decreased muscle fiber cross-sectional area, protein content, muscle strength, and increased insulin resistance [1]. Muscle atrophy occurs in cachexia, a comorbidity of abnormal conditions such as cancer, AIDS, congestive heart failure, and chronic obstructive pulmonary disease (COPD). It also occurs in sarcopenia, a decrease in muscle mass and strength associated with aging [2].

Although the causes of muscle atrophy are not fully understood, numerous factors contributing to the deterioration of muscle atrophy have been found through recent studies. Among these, decreased alpha motor neuron numbers, increased inflammatory cytokinesis, and decreased hormonal function are considered important factors in its pathogenesis [3].

Meanwhile, according to research by Alfonso et al. [4], the prevalence of sarcopenia in senior citizens aged 60 to 70 years was found to be 5-13% and 50% in patients over 80 years. Around the world, the population over 60 years was estimated to be about 60 million in the year 2000 and has been projected to be about 1.2 billion by 2025 and 2 billion by 2050. On condition that the current average prevalence of muscle loss is maintained, at least 50 million people to date and about 200 million people in the next 40 years will be affected by sarcopenia.

In complementary and alternative medicine, symptoms of muscular atrophy are treated using acupuncture, chuna treatment, and herbal medicine. In addition to these clinical treatments, many studies on complementary and alternative medicine (CAM) therapies for muscular atrophy have been conducted recently, but the results in literature have been insufficient. Against this background, we performed a literature review of CAM on muscular atrophy to establish a research model and suggest a direction for future research.

2. Method

2.1. Search Strategies

We conducted this literature review of in vivo/in vitro studies through Korean and foreign electronic database searches. Foreign databases used included PubMed, Cochrane Library, China National Knowledge Infrastructure (CNKI), and Wanfang MED. Domestic databases searched included Korean Traditional Knowledge Portal (KTKP), Oriental Medicine Advanced Searching Integrated System (OASIS), Research Information Services (RISS), National Assembly Library, and the Korean studies information Service System (KISS). In the Korean databases, “muscular atrophy”, “muscle loss”, and “complementary and alternative medicine” were used as search terms. In CNKI and Wanfang MED, we used cross-language searches and related search terms which were “muscle atrophy”, “muscle loss”, and “肌肉減少”.

The search strategy used in the searches in PubMed and the Cochrane Library was based on a combination of medical subject headings outlined in Table 1. The searches were conducted independently by two investigators (SM Jeong, YC Park) who retrieved relevant studies published before August 2018. After retrieving the articles, we extracted and classified the data by animal or cell models, intervention type (herbal medicine, acupuncture, and moxibustion), and outcome measures (muscle mass, strength, and histological and/or biochemical measurements). The extracted data was then verified by the third author (YH Baek). Disagreements were resolved by consensus through face-to-face discussions among the three authors.

Table 1: Search strategy.

#1
Muscular atrophy

#2
Muscle mass loss

#3
Muscle weight loss

#4
Muscle wasting

#5
Sarcopenia

#6
#1 or #2 or #3 or #4 or #5

#7

#8
Acupoint

#9

#10
Moxibustion

#11
Moxa

#12
Chinese medicine

#13
TCM

#14
Traditional medicine

#15
Kampo medicine

#16
Conservative therapy

#17
Complementary medicine

#18
#7 or #8 or #9 or #10 or #11 or #12 or #13 or #14 or #15 or #16 or #17

#19
#6 and #18

2.2. Study Selection

The inclusion criteria for the literature review were as follows: (1) articles on complementary and alternative medicine treatments for muscular atrophy and (2) in vivo or in vitro studies, while the exclusion criteria included the following: (1) clinical trial; (2) articles that were not original; (3) articles that were not in English, Korean, or Chinese; (4) duplicate studies. We also excluded studies that did not focus on muscle loss or muscle cell loss and those which did not use complementary and alternative medicine treatment. Full articles meeting the inclusion criteria were retrieved and read carefully.

3. Results

3.1. Literature Search

The search initially yielded 973 articles out of which duplicates were eliminated. After screening the titles, 872 articles were excluded due to a lack of adequate coverage of the topic of interest, and after full text assessment, 57 additional articles were excluded for one or more of the following reasons: (1) articles that were not based on original research; (2) articles that did not involve in vivo or in vitro studies; and (3) abstracts and comments. Finally, 44 articles were included in our literature review (Figure 1).

Figure 1: Study flow diagram.

3.2. In Vivo Studies

A total of 36 articles (27 of which were in vivo only and 9 of which were in vivo with in vitro studies) were classified as in vivo studies in our review.

3.2.1. Animal Model Species

The most commonly used model was the Sprague-Dawley rat which was used by 22 out of the 36 studies. C57BL/6 mice were used in 6 studies, BALB/c mice were used in 2 studies, and DBA/1 J mice, Kunming mice, and SPF/VAF mice were used in one study each. Three papers did not mention which animal models were used.

There were variations in the ages of the animals used in the studies, with 16-, 12-, 10-, 9-, 8-, 7-, and 6-week-old animals being used in 1, 2, 11, 1, 6, 1, and 7 studies, respectively. In one study, the ages of animals used in the test group differed from that of the control group, being 5 and 19 months, respectively. With regard to the sex of the animals, male rats were predominantly used, featuring in 30 studies, while one study used only female rats and one study used a combination of male and female animals. The other studies did not mention sex of the animals.

In order to induce muscular atrophy, various disease models were used in the studies. The most commonly used model for muscular atrophy was the hindlimb suspension (HS) method, developed by Morey-Holton and Wronski [49]. HS rat model was used in 7 of the 36 studies. The next commonly used model was nerve damage-induced muscular atrophy model which was used in 6 studies. Among these studies, direct injury to the sciatic nerve or the peroneal nerve was used to cause atrophy. The chronic kidney disease (CKD) model, in which induction was done by 5/6 nephrectomy was used in 5 studies. The alcohol-induced muscular atrophy model, transgenic model, and the cancer-induced cachexia model (C26-colon-adenocarcinoma implanted) were used, and each of these models was used in three of the 36 studies reviewed. In two studies, diabetes was induced by the administration of streptozotocin to evaluate muscular dystrophy due to diabetes. There were 2 studies using stroke models (middle cerebral artery occlusion, MCAO) and one study for each of the following models: chronic obstructive pulmonary disease (COPD), collagen-induced arthritis (CIA), dexamethasone-induced atrophy, spinal cord injury, and the aging models (Figure 2).

Figure 2: Animal models of in vivo studies.

3.2.2. Interventions

The most common types of intervention were herbal medicines which were used in 28 studies. In addition, there were 7 studies using electroacupuncture and one study using moxibustion (Figure 3). The treatment periods were 12 days in 2 studies, 2-4 weeks in 24 studies, 1-6 months in 8 studies, and 38 weeks in 1 study. One study did not limit the treatment period.

Figure 3: Interventions of in vivo studies.

3.2.3. Outcomes

Muscle mass, the most common primary outcome, was investigated in 28 out of the 36 studies. All except one reported a significant increase in muscle mass. Ten articles investigated muscle function, all of which reported significant increases in muscle strength (Tables 2 and 3).

Table 2: Summary of articles on complementary and alternative medicine therapies for muscular atrophy (in vivo).

First Author (year) (Ref)
Design
Origin
Group / Sample-Size (n)
Sample Model (Age) (M/F)
Duration
Outcome Measures
Quantity and Type of Intervention
Main outcomes

Onda A 2011 [5]
In vivo
Japan
Total n = 28
control (7)
HS (7)
HS + MA (7)
HS + EA (7)
Hindlimb suspension (HS) rat model
(C57BL/6, 8 wk, M)
2 wk
(1) Muscle weight/body weight
(2) Cross sectional area (CSA)
(3) Muscle-proteolytic genes
(4) Protein synthesis markers
MA (manual acupuncture): 30 min on the gastrocnemius, 5 mm insert
EA (electro-acupuncture): 30 min on the gastrocnemius, 5 mm insert, 1 Hz, 6.5 mA
1/day for 2wk
(1) Muscle/body weight:
HS < HS+MA (7%, p<0.05)
HS < HS+EA (10%, p<0.001)
(2) CSA: HS > HS+EA (p<0.05)
(3) Atrogin-1↓, MuRF1↓ in EA (p<0.01 vs. HS)
Atrogin-1↓ in MA (p<0.01 vs. HS)
(4) Akt1↑, TRPV4↑ in MA (p<0.05 vs. HS)

Su Z
2015
[6]
In vivo
China
Total n = 48
control (12)
LFES (12)
Diabetes (12)
Diabetes + LFES (12)
Streptozotocin-induced diabetic mouse model
(C57BL/6, 8-10 wk, M)
2 wk
(1) Muscle grip function
(2) Muscle weight/body weight
(3) Muscle regeneration proteins
(4) Protein synthesis markers
LFES (Low-frequency electric
stimulation):
positive point at GB34,
negative point at ST36
20 Hz, 1 mA for 15 min
1/day for 2wk
(1) Muscle grip function: DM + LFES > DM (p<0.05)
(2) Muscle weight (Soleus, Extensor digitorum longus): DM + LFES > DM (p<0.05)
(3) Pax7↑, MyoD↑, myogenin↑, eMyHC↑ (p<0.05 vs. DM)
(4) IGF-1↑, p-Akt↑, mTOR↑, p70S6K↑ (p<0.05 vs. DM)

Dong Y 2015
[7]
In vivo
China
Total n =72
Control + Saline (12)
Control + BJ (12)
Control + AP (12)
COPD + Saline (12)
COPD + BJ (12)
COPD + AP (12)
Klebsiella pneumoniae & cigarette smoke-induced COPD rat model
(Sprague-Dawley (SD) rat, 2 mo, M/F)
12 wk
(1) Muscular tension
(2) Muscular fatigue index
(3) Expressions of Bnip3 and Cyto-C in muscle tissues
BJ: Bufei Jianpi granules
(5 g·kg⁻¹·d⁻¹)
AP: Aminophylline
(2.3 mg·kg⁻¹·d⁻¹)
Intragastrically inserted
(1) Muscular tension: BJ > Saline, AP (p<0.05)
(2) Muscular fatigue: BJ < Saline, AP (P<0.05)
(3) Bnip3↓, CytoC↓ (p<0.05 vs. Saline, AP)

Zhuang P 2016 [8]
In vivo
China
Total n = 60
Normal + Water (C) (20)
Tumor + Water (M) (20)
Tumor + ZBHP (20)
C26-colon- adenocarcinoma-implanted mice
(C57BL/6, 4-6 wk, M)
19 d
(1) Muscle weight
(2) Muscle function
(3) Pro-inflammatory cytokines
(4) Atrophy-related genes
(5) IGF-1/Akt and autophagy pathway
ZHBP: Zhimu (Rhizoma Anemarrhena) and Huangbai (Cortex Phellodendri) 1:1 extracted with ethanol
104 mg/kg/day, oral intake
(1) Muscle weight: ZHBP > M (p<0.05)
(2) Grip-strength: ZHBP > M (p<0.01)
(3) TNF-α, IL-6: ZHBP < M (p<0.05)
IGF-1: ZHBP > M (p<0.01)
(4) Atrogin-1↓, MuRF1↓ (p<0.05 vs. M)
(5) SRIT1↑, p-Akt↑, FOXO3↓ (p<0.05 vs. M)

Kishida Y 2014 [9]
In vivo
Japan
Total n = 41
SAMP8 + N (10)
SAMP8 + GJG (10)
SAMR1 + N (10)
SAMR1 + GJG (11)
Senescence-accelerated rat model (SAMP8)
Senescence-accelerated aging-resistant rat model (SAMR1)
(7 wk, M)
38 wk
(1) Muscle fiber size
(2) Myofiber balance (fast/slow)
(3) Glycogen synthesis proteins
(4) Muscle atrophy proteins
GJG: Go-sha-jinki-Gan
4% (w/w) GJG daily for 38 wk
N (Control): normal diet
(1) Muscle fiber: P8+N < P8+GJG (p<0.0001)
(2) Fast skeletal muscle: P8+N <P8+ GJG (p<0.0001)
p-AMPK↑, PGC-1α↑ in P8+GJG
(3) IGF-1↑, p-Akt↑, p-GSK3β↑
(4) p-FoxO4↑, MuRF1↓, TNF-α↓

Hu L
2015 [10]
In vivo
China
Total n = 48
Sham (Sham op) (12)
Sham-LFES (12)
CKD (12)
CKD-LFES (12)
5/6-nephrectomized rat model (mice with chronic kidney disease) (n r, n r, n r)
15 d
(1) Muscle mass (soleus & extensor digitorum longus)
(2) Grip strength meter
(3) Synthesis-related proteins
(4) IGF-1 and MGF
LFES: Low-frequency electric
Stimulation acupuncture
positive point (GB34)
negative point (ST36), 20Hz, 1mA 15 min 1/day for 15 d needles: 0.25 mm (diameter)
(1) Muscle mass: Sham ≒ Sham-LFES
CKD < CKD-LFES (p<0.05)
(2) Muscle function: CKD < CKD-LFES (p<0.05)
(3) p-Akt, mTOR, p70S6K: CKD < CKD-LFES (p<0.05)
(4) IGF-1, MGF: CKD < CKD-LFES (p<0.05)

Nakashima Y
2014 [11]
In vivo
Japan
Total n = 16
Control (8)
CSD (8)
ALDH22 Tg rat model
(selectively decrease ALDH2 activity)
(C57BL/6 mice, n r, M)
6 mo
(1) Oxidative stress marker
(2) Muscle tissue injury marker
(3) Body weight
(4) Gastrocnemius cell size
(5) Mitochondrial cytochrome C oxidase activity
CSD: Chlorella-supplemented diet 1% for 6 mo

Control: fed basic diet
(1) Urinary isoprostane: CSD < Control (after 4 mo, p<0.05)
MDA, HAE: CSD < Control (p<0.01)
(2) CPK activity: CSD < Control (p<0.05)
CKMB activity: CSD < Control
(3) Body weight: CSD > Control (after 4 mo, p<0.05)
(4) Cell size: CSD > Control (p<0.05)
(5) Cyto-C oxidase activity: CSD < Control (p<0.01)

Kim MJ
2012
[12]
In vivo
Korea
Total n = 12
Control (4)
CIA (4)
CIA+Moxi (4)
Collagen-induced arthritis (CIA) rat model (Inj of bovine type II collagen)
(DBA/1J mice, 6 wk, M)
3 wk
(1) Cross-sectional area
(2) Phospho-ERK1/2
(3) Myostatin protein
(4) IGF-1 mRNA
Moxi: Moxibustion BL23 (shenshu), ST36 (zusnali) on both sides
5 times/day every other day for 3 wk
Kangwha-moxi cone 0.025g per 1point
(1) CSA: Control > CIA+Moxi > CIA (p<0.05)
(2) phospho-ERK1/2: CIA > CIA+Moxi
(3) Myostatin protein: CIA > CIA+Moxi
(4) IGF-1: CIA+Moxi > CIA

Kim JW
2015 [13]
In vivo
Korea
Total n = 48
Control (8)
Dexa control (8)
Dexa + OM (8)
Dexa + FS125 (8)
Dexa + FS250 (8)
Dexa + FS500 (8)
Dexamethasone-induced muscle atrophy mice
(SPF/VAF mice, n r, n r)
24 d
(1) Muscle mass
(2) Muscle strength
(3) Serum biochemistry
(4) Antioxidant defense factor
(5) mRNA expression
FS: Fructus Schisandrae extract 125, 250, 500mg/kg, 1/day for 24 d oral intake
OM: Oxymetholone 50 mg/kg
(1) Muscle mass
(a) Body weight: Dexa < FS125 < FS250 < OM < FS500 (p<0.01)
(b) Calf, Gastrocnemius thickness: Dexa < FS 125 < FS250 < FS 500 < OM (p<0.01)
(2) Muscle strength: Dexa < FS250, FS500 (p<0.01)
(3) Serum creatine↓, CK↓, LDH↑ (p<0.01 vs. Control)
(4) MDA↓, ROS↓, GSH↓, SOD↓, CAT↓
(5) Atrogin-1↓, MuRF1↓, SIRT1↓, PI3K↑, Akt1↑, A1R↑ (p<0.05 vs. control)

Zhang J
2014 [14]
In vivo
China
Total n = 45
Normal (C) (15)
Diabetes (M) (15)
Diabetes + ZB (15)
Insulin deficiency rat model by low-dose STZ injection
(C57BL/6, 12 wk, M)
6 wk
(1) Muscle weight
(2) Muscle function
(3) Myofiber CSA
(4) IGF1, Akt/mTOR/FoxO3 signal pathways
ZB: Zhimu-Huangbai (1:1) herb pair 0.1ml/10g, 1/day for 6 wk
C, M: Normal saline treated
(1) Muscle (quadriceps) weight: ZB > M (p<0.05)
(2) Muscle strength: ZB > M (p<0.01)
(3) CSA: ZB > M (p<0.05)
(4) IGF-1↑, Akt↑, mTOR↑, p-S6K1↑, FoxO3↓ (p<0.05 vs M)

Jang SO
2009 [15]
In vivo
Korea
Total n = 48
Control (24)
Sample (PR) (24)
Sciatic nerve-damaged rat model
(SD rat, 10 wk, M)
12 d
(1) Muscle weight
(2) Cross-sectional area
(3) Bax, Bcl-2
PR: Puerariae Radix extract, 25.0mg/100g, 1/day for 12 d oral intake
(1) Muscle weight: Control < Sample (p<0.05)
(2) CSA: Control < Sample (p<0.05)
(3) Bcl-2↑, Bax↓ (p<0.05)

Kim BH 2016 [16]
In vivo
Korea
Total n = 30
Normal (10)
EtOH (10)
EtOH + DKEJ (10)
EtOH-treated rat model
(SD rat, 10 wk, M)
8 wk
(1) Body weight
(2) Muscle weight
(3) Cross-sectional area
DKEJ: Daekumeumja
28.0mg/100g, 1/day for 8 wk
(1) Body weight: EtOH < EtOH + DKEJ (p<0.05)
(2) Muscle weight: EtOH < EtOH + DKEJ (p<0.05)
(3) CSA: EtOH < EtOH + DKEJ (p<0.05)

Cho JH
2008 [17]
In vivo
Korea
Total n = 36
Sham-OP (12)
Control (OP) (12)
OP + EC (12)
Sciatic nerve-damaged rat model
(SD rat, 10 wk, M)
12 d
(1) Muscle weight
(2) Cross-sectional area
(3) Bax, Bcl-2
EC: Eucommiae Cortex extract 170mg/100g, 1/day for 12d
(1) Muscle weight: Sham-OP > EC > Control (p<0.05)
(2) CSA: Sham-OP > EC > Control (p<0.05)
(3) Bax↓, Bcl-2↑

Lee CW 2007 [18]
In vivo
Korea
Total n = 24
Sham (8)
Control (MCAO) (8)
Sample (MCAO + DR) (8)
Middle cerebral artery occlusion (MCAO) stroke rat model
(SD rat, 10 wk, M)
25 d
(1) Muscle fiber type
(2) Cross-sectional area
(3) MHC-II
(4) MyoD expression
DR: Dipsaci Radix
184.4 mg/100g, 1/day for 25d, oral intake
(1) Muscle fiber type (type-I): Control < Sample (p<0.01)
(2) CSA: not significant
(3) MHC-II↓
(4) MyoD: Control < Sample (p<0.01)

Han SW
2008
[19]
In vivo
Korea
Total n = 18
Sham (6)
Control (6)
Sample (6)
MCA occlusion stroke rat model
(SD rat, 10 wk, M)
4 wk
(1) Muscle fiber type
(2) Cross-sectional area
(3) MyoD expression
DR: Dipsaci Radix
184.4mg/100g, 1/day for 4 wk, oral intake
(1) Muscle fiber type: type-I ↑, type-II ↓ (p<0.05 vs. control)
(2) CSA: control < Sample (p<0.05)
(3) MyoD↑ (p<0.05 vs. control)

Kim BH 2017 [20]
In vivo
Korea
Total n = 30
Normal (10)
EtOH (10)
EtOH + PR (10)
Alcohol-induced (EtOH) muscle atrophy rat model
(SD rat, 10 wk, M)
4 wk
(1) Muscle weight
(2) Cross-sectional area
(3) Bcl-2, Bax
PR: Pueraria radix 4.6mg/100g, 1/day for 4 wk, oral intake
(1) Muscle weight: EtOH + PR > EtOH (p<0.05)
(2) CSA: EtOH + PR > EtOH (p<0.05)
(3) Bcl-2↑, Bax↓ (p<0.05 vs. EtOH)

Soh KS 2009 [21]
In vivo
Korea
Total n = 24
Normal (6)
Control (6)
HS (6)
HS + KS (6)
Hindlimb suspension rat model
(SD rat, 6 wk, M)
2 wk
(1) Muscle weight
(2) IGF-1 protein
(3) Myogenin protein
(4) MyoD protein
KS: KangwhalSokdan-tang
1 mg/100g, 3 times/1day orally
(1) Muscle weight: HS < HS+KS (p<0.001)
(2) IGF-1: HS < HS+KS (p<0.05, in Type I)
(3) Myogenin: not significant
(4) MyoD: HS < HS+KS (p<0.05 in Type I)

Kim BH 2016 [22]
In vivo
Korea
Total n = 30
Normal (10)
EtOH (10)
EtOH + SHSGS (10)
Alcohol-induced (EtOH) muscle atrophy rat model
(SD rat, 10 wk, M)
4 wk
(1) Muscle weight
(2) CSA
(3) Apoptotic factor
SHSGS: Shihosogan-san
31.5 mg/100g, 1/day for 4 wk, orally
(1) Muscle weight: not significant
(2) CSA: not significant
(3) Bcl-2↑, Bax↓ (p<0.05 vs. EtOH)

Kim BH 2017 [23]
In vivo
Korea
Total n = 20
Control (CON) (10)
DYJ (10)
Hindlimb suspension rat model
(SD rat, 10 wk, M)
2 wk
(1) Muscle weight
(2) CSA
(3) Apoptotic factor
DYJ: Daeyeoung-jeon 259.6mg/100g/day orally
CON: Saline, orally
(1) Muscle weight: CON < DYJ (p<0.05)
(2) CSA: CON < DYJ (p<0.05)
(3) Bax↓, Bcl-2↑ (p<0.05 vs. CON)

Kim BH 2017 [24]
In vivo
Korea
Total n = 20
CON (10)
DGBHT (10)
Hindlimb suspension rat model
(SD rat, 10 wk, M)
2 wk
(1) Muscle weight
(2) CSA
(3) Malondialdehyde (MDA)
(4) Cu/Zn-SOD activation
DGBHT: Dangguibohyul-tang 236.7mg/100g/day orally
CON: Saline, orally
(1) Muscle weight: CON < DGBHT (p<0.05)
(2) CSA: CON < DGBHT (p<0.01)
(3) MDA: no significant difference
(4) Cu/Zn-SOD: CON < DGBHT (p<0.05)

Wang D 2017 [25]
In vivo
China
Total n = 30
CON (10)
JPYS (10)
Sham-OP (10)
5/6 nephrectomized rat model (SD rat, n r, M)
6 wk
(1) Renal function
(2) Muscle weight
(3) CSA
(4) Protein synthesis and protein degradation
(5) Ubiquitin-proteasome system and FoxO3a activation
(6) Mitochondrial biogenesis proteins
(7) Muscle autophagy/mitophagy pathway
(8) Mitochondrial dynamics
JPYS: Jian-Pi-Yi-Shen decoction, 10.89mg/kg/day orally
(1) BUN, Creatinine: CON > JPYS (p<0.001)
(2) Muscle weight: CON < JPYS (p<0.05)
(3) CSA: CON < JPYS (p<0.05)
(4) Protein synthesis↑, degradation↓ (p<0.05 vs CON)
(5) Atrogin-1↓, MuRF-1↓, p-FoxO3a↑, FoxO3a↓ (p<0.05 vs. CON)
(6) Cox IV↑, NRF-1↑, PGC-1α↑ (p<0.05 vs. CON)
(7) LC3II/LC3I ratio↓, Beclin-1↓, P62↓, PINK1↓, Parkin protein level↓ (p<0.05 vs. CON)
(8) Fis1↓, Mfn2↑ (p<0.01 vs CON), Drp-1↓, OPA-1↑ (p<0.05 vs. CON)

Su Z 2017 [26]
In vivo
China
Total n = 36
Sham-OP (9)
Sham+LFES (9)
CKD (9)
CKD+LFES (9)
5/6 nephrectomized rat model (C57/BL6 mice, 2-4 mo, M)
2 wk
(1) Autophagosome-proteolysis pathway
LFES: positive point-GB34, negative point-ST36
20Hz, 1mA for 15min
(1) Bnip3↓, Beclin-1↓, LC3II/I ratio↓ (p<0.05 vs. CKD)

Zhou L 2018 [27]
In vivo
China
Total n = 56
Sham-OP (8)
Model (DSMA) (8)
CON-siRNA +BYHWT (8)
ANGPTL4-siRNA +BYHWT (8)
BYHWT low (8)
BYHWT moderate (8)
BYHWT high (8)
Denervated-dependent skeletal muscle atrophy (DSMA) rat model
(SD rat, 8-10 wk, M)
2 wk
(1) ANGPTL4 in pathogenesis of DSMA (on Anti-inflammatory effect)
(2) Muscle cell apoptosis
(3) NF-кB and MURF1 expression
BYHWT: Buyang Huanwu Tang
(high: solution diluted 2X / moderate: 4X / low: 8X), 2ml every day, orally
Model: DSMA + saline
ANGPTL4: angiopoietin-like protein 4
(1) Inflammatory Cells: Model > ANGPLT4-siRNA+BYHWT > CON-siRNA+BYHWT (p<0.05)
(2) Cell apoptosis: Model > BYHWT-low > BYHWT-moderate > BYHWT-high (p<0.01 vs. Model)
(3) NF-кB p65, MURF1: Model > BYHWT-low > BYHWT-moderate > BYHWT-high (p<0.05 vs. Model)

Yu J 2017 [28]
In vivo
China
Total n = 54
NOR (6)
SNI 1wk, 2wk, 4wk, 6wk (6 each)
NOR+EA 4wk, 6wk (6 each)
SNI+EA 4wk, 6wk (6 each)
Penicillin injection-induced sciatic nerve injury (SNI) rat model
(SD rat, 7-9 wk, M)
2 wk/ 4 wk
(1) Sciatic nerve functional indices (SFI)
(2) Muscle weight
(3) Muscle fibre CSA
(4) mRNA expression of agrin, AChR-ε and AChR-γ
EA: Electro-acupuncture at GB30 (positive) and ST36 (negative)
5Hz, 2mA for 30min
1 course: alternate days, three times a week for 2 weeks
2 course: alternate days, three times a week for 4 weeks
1w, 2w, 4w, 6w: euthanased at 1,2,4,6weeks
(1) SFI: SNI < SNI+EA (p<0.05)
(2) Muscle weight: SNI < SNI+EA (p<0.05)
(3) CSA: SNI < SNI+EA (p<0.05)
(4) agrin↑, AChR-ε↑, AChR-γ↓ (p<0.05 vs. SNI)

Zhang YH
2017 [29]
In vivo
China
Total n = 72
SCI (18)
TANES (18)
EA (18)
Sham-OP (18)
Spinal cord transection surgery treated rat model (SD rat, n r, F)
4 wk
(1) Motor neurons of L3, L5
(2) Neurotransmitter synthetase (ChAT)
(3) Neurotrophin-3 (NT-3) expression
(4) Muscle weight
(5) CSA
TANES: Tail nerve electrical stimulation 2.5-8.0kHz(mid),
1-150Hz(low), 100mA, 20min 5times/week for 4weeks
EA: electroacupuncture, GV6, GV9, GV2, GV1, ST36, 60Hz for 1.05s and 2Hz for 2.85s, pulse width 0.5ms, 2min, every other day for 4weeks
SCI: spinal nerve injury
(1) Motor neuron L3: SCI < TANES, EA (p<0.05)
L5: SCI < TANES, EA (p<0.05)
(2) ChAT (choline acetyltransferase): SCI < TANES, EA (p<0.05)
(3) NT-3: SCI < TANES, EA (p<0.05)
(4) Muscle weight: SCI < TANES, EA (p<0.05)
(5) CSA: SCI < TANES, EA (p<0.05)

Zhou L 2017 [30]
In vivo
China
Total n = 60
Sham-OP (10)
Model (10)
BYHWT-low (10)
BYHWT-middle (10)
BYHWT-high (10)
MCB (10)
Peroneal nerve injury rat model (SD rat, n r, M)
10d / 21d
(1) NF-κB p65, MuRF1 gene expression in 10day
(2) NF-κB p65, MuRF1 gene expression in 21day
BYHWT: Buyang Huanwu Tang
(i) low: 3g/kg/day
(ii) middle: 6g/kg/day
(iii) high: 12g/kg/day
MCB: Mecobalamin 500μg/day
(1) NF-κB p65: Model > BYHWT-low > B-middle (p<0.05) > MCB > B-high (p<0.01 vs. model)
MuRF1: Model > BYHWT-low > B-middle (p<0.05) > B-high > MCB (p<0.01 vs. model)
(2) NF-κB p65: Model > BYHWT-low > B-middle (p<0.05) > MCB > B-high (p<0.01 vs. model)
MuRF1: Model > BYHWT-low > B-middle (p<0.05) > B-high > MCB (p<0.01 vs. model)

Cao R 2017 [31]
In vivo
China
Total n = 63
Sham-OP
Model
EA
groups divided into 7days, 14days, 21days each
Sciatic nerve injury rat model (SD rat, 2 mo, M)
7d / 14d / 21d
(1) Muscle cell apoptosis
(2) Apoptotic factor
EA: Electro-acupuncture at ST36 and BL57
5Hz, 1.5mA for 10min
once a day for 7d, 14d, 21d
(1) Cell apoptosis (7d, 14d, 21d): Model > EA (p<0.05)
(2) Bcl-2↑, Bax↓, Cyto-C↓, Caspase-3↓ in 14d, 21d (p<0.05 vs. Model)

n r: not reported.

Table 3: Summary of articles on complementary and alternative medicine therapies for muscular atrophy (in vivo + in vitro).

Authors
Design
Origin
Group / Sample Size (n)
Sample Model
Duration
Outcome Measures
Quantity and Type of Intervention
Main Outcomes

Kim AY
2016 [32]
In vivo/
In vitro
Korea
In vivo
Total n = 20
No tumor (5)
Tumor + Saline (5)
Tumor + SO50 (5)
Tumor + SO100 (5)

In vivo:
CT-26 s.c injection tumor-bearing mice
(BALB/c mice, 6 wk, M)

In vivo: 18 d

In vivo:
(1) Body weight
(2) Muscle weight
(3) NO, inflammatory cytokines
(4) phos-p38, IкBα, IKKαβ, STAT3

Sosiho-tang (SO)
In vivo:
(i) SO: fed 50 or 100 mg/kg,
days 10 to 27 after tumor inoculation
(ii) Control: fed saline

In vivo:
(1) Body weight: Normal > T + SO (100) > T + SO (50) > T + Saline
(2) Muscle weight: Normal ≒ T + SO (100) ≒ T+SO (50) > T + Saline
(3) NO: dose-dependently suppress (p<0.05 vs. control)
IL-6, IL-1α, TNF-α, IL-1β: T + Saline > T + SO (p<0.05)
(4) phos-p38↓, IкBα↓, IKKαβ↓, STAT3↓: T + Saline > T+SO

In vitro
CON
SO-0, -50, -100
In vitro:
CT-26-mediated C2C12 myoblast
In vitro: 48 h
In vitro:
(1) IL-6, TNF-α
(2) Muscle wasting & myotubes
In vitro:
(i) SO powder dissolved in 10% DS to 50 μg/ml, 100 μg/ml for 48 h
In vitro:
(1) IL-6, TNF-α: T + Saline > T+SO (10) > T+SO (50) >T+SO (100) (p<0.05 vs. control)
(2) Muscle wasting↓
Intact myotubes↑

Zhang ZK
2016 [33]
In vivo/
In vitro
China
In vivo:
Baseline (10)
Age-matched control (10)
HS (10)
L-ICT + HS (10)
H-ICT + HS (10)
W (10)
L-ICT + W (10)
H-ICT + W (10)
In vivo: Rats with or without wortmannin inj. (15 μm/kg/day) for 28 d HS
(SD rat, 3 mo, M)
In vivo: 28 d
In vivo:
(1) Mass outcome (muscle weight, fiber CSA)
(2) Muscle function
ICT: Icaritin
In vivo:
(i) Low ICT (L-ICT): 80 mg/kg/day
(ii) High-ICT (H-ICT): 120 mg/kg/day,
oral intake
In vivo:
(1) Mass outcome:
HS < L-ICT + HS < H-ICT + HS < Baseline (p<0.05)
W < L-ICT + W < H-ICT + W < Baseline (p<0.05)
(2) Functional outcome:
HS < L-ICT + HS < H-ICT + HS < Baseline (p<0.05)
W < L-ICT + W < H-ICT + W < Baseline (p<0.05)

In vitro:
CON
ICT 5, 10, 20
In vitro: Wortmannin (W) pre-incubated C2C12 cell

In vitro: 24 h

In vitro
(1) PI3K/Akt signaling proteins

In vitro: ICT 5 μM or 10 μM or 20 μM for 24 h

In vitro:
(1) PI3K-p110, p-Akt, p-mTOR, p70S6K, p-4EBP1:
ICT > ICT+W > W (p<0.05)
FOXO1, FOXO3a: ICT < ICT+W < W (p<0.05)
Atrogin-1, MuRF-1: ICT < ICT + wort < wort (p<0.05)
Atrogin-1, MuRF-1: Control > ICT10 > ICT20 (p<0.05 vs. CON)

Sung BK
2015
[34]
In vivo/
In vitro
Korea
In vivo:
Young-Control (YC)
Young-LE (YL)
Old-Control (OC)
Old-LE (OL)
(n = 4~6 per group)
In vivo:
Young SD rat (5 mo, M)
Old SD rat (18-19 mo, M)

In vivo:
35 d

In vivo:
(1) Muscle mass
(2) Muscle function
(3) Muscle CK activity

In vivo:
Loquat leaf extract (LE)
fed 50 mg/kg/day for 35 d

In vivo:
(1) Muscle mass: OL > OC (p<0.05)
(2) Muscle strength: OL > OC (p<0.05)
(3) CK activity: OL > OC (p<0.05)

In vitro:
CON
LE 0.25, 0.5, 1.0, 2.5
In vitro:
C2C12 myoblasts (untreated)
In vitro:
24 h
In vitro:
(1) C2C12 viability
(2) Myogenic proteins
(3) CK activity
(4) Akt/mTOR pathway
In vitro:
LE 0.25, 0.5, 1.0, 2.5 μg/ml for 24 h
In vitro:
(1) Cell viability: control < LE
(2) MyHC, MyoD: control < LE 0.25 < LE 0.5 < LE 1.0 < LE 2.5
(3) CK activity: control < LE 1.0 < LE 2.5 (p<0.01)
(4) PI3K, Akt, mTOR: control < LE

Lu L
2016 [35]
In vivo/
In vitro
China
In vivo
Total n = 160
Sham OP (SOP) (40)
OP (40)
OP + APS (40)
SOP + APS (40)
In vivo:
5/6 nephrectomized
SD rats (SD rat, 6 wk, M)
In vivo:
155 d

In vivo:
(1) Body weight
(2) Cross-sectional area
(3) p-Akt/mTOR, MuRF1/MAFbx and Autophagy signaling
(4) Amino acid carriers
(5) Pro-inflammatory & Oxidative factor
In vivo:
Control: Normal diet, Sham OP
APS: Normal diet with 2% Astragalus polysaccharide
In vivo:
(1) Body weight: OP < OP+APS < SOP (p<0.05)
(2) Mean CSA: OP + APS > OP (p<0.05)
(3) p-Akt, mTOR: OP < OP + APS (p<0.05)
MuRF1, MUFbx: OP > OP + APS (p<0.05)
Atg7, LC3B: OP > OP + APS (p<0.05)
(4) SLC38A2, ATF4: OP < OP + APS (p<0.05)
(5) TNF-α, IL-15, CRP: OP > OP + APS (p<0.05)
MDA: OP > OP + APS (p<0.05)
SOD: OP < OP + APS (p<0.05)

In vitro
Control
TNF-α
TNF-α + APS 0.05, 0.1, 0.2, 0.5, 1, 2
In vitro:
TNF-α treated C2C12 cell
In vitro:
48 h
In vitro:
(1) Myotube diameter
(2) Akt/mTOR, ubiquitin proteasome, autophagy signaling
In vitro:
APS: 0.05, 0.1, 0.2, 0.5, 1, 2 mg/mL APS
80 ng/mL TNF-α treated
In vitro:
(1) Myotube diameter: Control < APS (p<0.05)
(2) p-mTOR: Control < APS (p<0.05)
LC3B-II/LC3B-I ratio: Control > APS (p<0.05)

Cho SG 2018 [36]
In vivo/ In vitro
Korea
In vivo
Total n = 48
normal (8)
CON (8)
SC 20 (8)
SC 100 (8)
SSLE 20 (8)
SSLE 100 (8)

In vivo:
Hindlimb suspension rat model (SD rats, 6 wk, M)

In vivo: 21 d

In vivo:
(1) Muscle weight
(2) Muscle strength
(3) CSA

SC: Schisandra chinensis (Turcz.) Baill
LC: Lycium chinense Mill
EU: Eucommia ulmoides Oliv
SSLE: 2:1:1-SC:LC:EU herb pair
SLE: 1:1:1-SC:LC:EU

In vivo: (orally)
(i) 20: 20mg/kg
(ii) 100: 100mg/kg

In vivo:
(1) Muscle weight
(a) Gastrocnemius: CON < SC20 < SC100 < SSLE20 < SSLE100 (p<0.001 ver CON)
(b) Soleus: CON < SC20 < SC100 (p<0.05) / CON < SSLE20 < SSLE100 (p<0.001)
(c) Tibialis ant: CON < SSLE100 (p<0.01)
(2) Muscle strength: CON < SC100, SSLE20 (p<0.01), SSLE100 (p<0.001)
(3) CSA: CON < SC100, SSLE20, SSLE100 (p<0.001)

In vitro
TNF
LC
EU
SC
SLE
SSLE
In vitro:
TNF-α treated C2C12 cell
In vitro:
24 h

In vitro:
(1) Myotube diameter
(2) Protein synthesis (ubiquitin-proteasome system)
In vitro: 200 μg/ml
In vitro:
(1) Myotube diameter: CON < LC, EU, SC, SLE, SSLE (p<0.001)
(2) atrogin-1↓ with SC, SLE, SSLE (p<0.001 vs CON)
(3) MuRF-1↓ with LC, EU, SLE, SSLE (p<0.001 vs CON)
(4) MyoD↑ with LC, EU, SC, SLE, SSLE (p<0.001 vs CON)
(5) Myogenin↑ with EU, SC, SLE, SSLE (p<0.001 vs CON)
(6) p-Akt ↑, p-mTOR↑ with LC, EU, SC, SLE, SSLE (p<0.01 vs CON)

Zhu M 2017 [37]
In vivo/ In vitro
China
In vivo
Total n = 24
CON (8)
HS (8)
BZ (8)

In vivo:
Hindlimb suspension rat model (Kunming mice, 8 wk, M)

In vivo: 21 d

In vivo:
(1) Muscle weight
(2) CSA
(3) Muscls strength

In vivo:
BZ: Bu Zhong Yi Qi decoction 5.93mg/g/day orally

In vivo:
(1) Muscle weight
(a) Gastrocnemius: HS < BZ (p<0.05)
(b) Soleus: HS < BZ (p<0.05)
(2) CSA: HS < BZ (p<0.05)
(3) Muscle strength: HS < BZ (p<0.01)

In vitro
RS
BZ
In vitro:
C2C12 myoblasts (untreated)
In vitro:
n r
In vitro:
(1) NCoR1 (nuclear receptor corepressor 1)
(2) Myogenesis
In vitro:
RS: rat serum
BZ: Bu Zhong Yi Qi decoction
In vitro:
(1) NCoR1↓ (p<0.001 vs RS)
(2) Pax7↑ (p<0.05), Myogenin↑, MyHC↑ (p<0.01)

Geng Z 2017 [38]
In vivo/ In vitro
China
In vivo
Total n = 32
NOR (8)
CON (8)
APS (8)
KT (8)

In vivo:
5/6 nephrectomized rat model (SD rat, 7-8 wk, M)

In vivo:
6 wk

In vivo:
(1) Atrogin and ubiquitin

APS: Astragalus polysaccharide, 3g/kg/day for 6 weeks, intraperitoneally / in vitro: 15 mg/1
KT: ketosteril (α-ketoacid tablets), 1ml/200g/day for 4 weeks, intravenously
CON: saline, 3g/kg/day for 6weeks, intraperitoneally
NOR: Sham-OP
PDTC: pyrrolidine dithiocarbamate 50 μmol/1
In vivo:
(1) Atrogin-1: APS < KT < CON (p<0.05 vs CON)
Ubiquitin: APS < KT < CON (p<0.05 vs CON)

In vitro
TNF
TNF+APS
TNF+PDTC
In vitro:
TNF-α treated rat L6 myoblasts
In vitro:
48 h
In vitro:
(1) Atrogin and ubiquitin
(2) Muscle cell diameter
In vitro:
(1) Atrogin-1↓, Ubiquitin↓ in APS (p<0.05 vs CON)
(2) Cell diameter↑ in APS (p<0.05 vs CON)
(3) Atrogin-1↓, Ubiquitin↓ in PDTC (p<0.05 vs CON)
(4) Cell diameter↑ in PDTC (p<0.05 vs CON)

Kim AY 2018 [39]
In vivo/ In vitro
Korea
In vivo
Total n = 15
CON (5)
SGE10 (5)
SGE50 (5)

In vivo:
CT-26 colon carcinoma-implanted mice (BALB/c mice, 6 wk, M)

In vivo: 15 d

In vivo:
(1) Body weight
(2) Muscle weight
(3) IL-6

SGE: herbal cocktail composed of Ginseng Radix alba, Atractylodis Rhizoma alba, and Hoelen

In vivo:
SGE 10mg/kg/day or 50mg/kg/day for 15days, orally
In vivo:
(1) Body weight: CON < SGE10 (p<0.01), SGE50 (p<0.05)
(2) Muscle weight: CON < SGE50 (p<0.01)
(3) Serum IL-6: CON > SGE10 > SGE50 (p<0.01)

In vitro
SGE 5
SGE 10
SGE 25
SGE 50
In vitro:
CT-26-mediated C2C12 myoblast
In vitro: 48 h
In vitro:
(1) Inflammatory cytokines
(2) NO production and MAPK/NF-κB activation
(3) Muscle cell proliferation protein
In vitro:
SGE 5, 10, 25, 50μg/mL, incubated for 48h
In vitro:
(1) IL-1β↓ (5,10,25,50 p<0.01), IL-6↓ (10,25,50 p<0.01),
TNF-α↓ (25 p<0.05, 50 p<0.01)
(2) NO↓ (10,25,50 p<0.01), iNOS↓ (25,50 p<0.01), p-p38↓,
p-ERK↓, p-JNK↓, p-IκBα↓ (25,50 p<0.01)
(3) MyH↑ (10,25,50 p<0.01)

Tseng YT
2017
[40]
In vivo/ In vitro
China
In vivo
Total n = 32
WT (wild-type) (8)
CON (8)
LWDH15 (8)
LWDH30 (8)
In vivo:
Survival motor neuron (SMN) deficiency-induced transgenic mice model (n r, n r, M)
In vivo: not limited

In vitro: 48 h
In vivo:
(1) SMN expression in muscle
(2) Muscle strength
(3) Body weight
LWDH: Liuwei dihuang water extract
In vivo: 15mg/kg/day, 30mg/kg/day, orally
In vivo
(1) Survival motor neuron expression: CON < LWDH30 (p<0.001)
(2) Hindlimb score: CON < LWDH30 (p<0.001)
(3) Body weight: WT > LWDH30 (p<0.01) > LWDH15 (p<0.05) > CON

In vitro
CON
LWDH 0.01, 0.1, 1, 10

In vitro:
NSC34 motor neuron-like cell (transfected to SMN deficiency)

In vitro:
(1) Apoptotic-related pathway
In vitro: 0.01, 0.1, 1, 10μg/mL
In vitro
(1) Bcl-2↑, cytochrome c↓, cleaved-caspase-3↓

(A) Hindlimb Suspension Model. In the study conducted by Akiko Onda et al., electroacupuncture (E-AT) inhibited the expression of the MuRF-1 gene. E-AT also elevated the expression of Akt1 and TRPV4 [5]. In the study by Zhang ZK et al., icaritin extract was used which inhibited reduced phosphorylation of PI1K-p110, thereby promoting protein synthesis. In addition, the extract inhibited muscle atrophy through modulation of the FoxO3a and FoxO1, the O subclasses of the forkhead family of transcription factors [33]. In the study by Soh KS et al., after using KangwhalSokdan-tang (KWSDT), the ratio of type I muscle fiber/type II fiber was increased showing that KWSDT inhibited early muscular atrophy. IGF-1 and MyoD were also measured and increasing of these key myogenic factors was involved in the improvement of muscle mass [21].

In Cho SG et al., the combination of Schisandra chinensis Baill, Lycium chinense Mill, and Eucommia ulmoides Oliv inhibited muscular atrophy and increased muscle strength and cross-sectional area of muscle fiber [36]. Zhu M et al. also reported the similar effects on muscular atrophy by using Bu Zhong Yi Qi decoction [37].

Bax and Bcl-2 were measured in Kim BH’s study. Daeyeoung-jeon extract significantly reduced the immunoreactivity of Bax and increased Bcl-2 in gastrocnemius muscle [23]. In another study by Kim BH, Dangguibohyul-tang (Dangguibuxuetang) extract significantly enhanced the antioxidant enzyme, Cu/Zn-SOD which inhibited disuse muscular atrophy by suppressing oxidative damage [24].

(B) Nerve Damaged Model. In the studies using nerve damaged model, one study provided treatment with Radix Puerariae extract and the other used Radix Dipsaci extract. Both studies measured Bcl-2 and Bax. While Radix Puerariae extract was found to significantly inhibit Bax but not Bcl-2 [15], Radix Dipsaci extract significantly inhibited both Bax and Bcl-2 expression [17].

In the study by Zhou L. et al., the result indicated that Buyang Huanwu Tang (BYHWT) decreased inflammatory cells through the activation of angiopoietin-like protein 4 (ANGPTL4) and inhibited muscle cell apoptosis in the denervated-dependent skeletal muscle atrophy model. The effect of BYHWT was mediated by increased expression of NF-κB and MuRF-1 [27]. Another study by Zhou L. et al., BYHWT increased the NF-κB p65 and MuRF1, too [30].

Yu J. et al. applied E-AT on penicillin injection-induced sciatic nerve injury model and the treatment alleviated muscular atrophy by upregulating agrin and acetylcholine receptor-ε (AChR-ε), and downregulating AChR-γ associated in neuromuscular transmission [28]. In Cao R. et al., E-AT on sciatic nerve injury inhibited muscle cell apoptosis by suppressing Bax, cytochrome C, and caspase-3 [31].

(C) Stroke-Induced Model. In the studies by Lee et al. and Han et al., the Radix Dipsaci extract inhibited the “slow-to-fast shift" phenomenon in muscle fibers and MHC-II expression while increasing MyoD expression and thereby significant efficacy in muscle recovery [18, 19].

(D) Diabetes-Induced Model. Insulin-like growth factor 1 (IGF-1) was the main factor measured in both studies using diabetes-induced model. In the study by Su Z et al., low-frequency electroacupuncture stimulation (LFES) promoted IGF-1 [6]. Additionally, LFES increased Pax7 genes, MyoD, myogenin, and eMyHC. In a study by Zhang J. et al., the Zhimu-Huangbai (1:1) herb pair was used, which promoted IGF-1 and inactivated FOXO3 protein [14].

(E) Chronic Kidney Disease-Induced Model. In a study by Hu L. et al., LFES promoted the IGF-1 signaling pathway by decreasing microRNA-1 and microRNA-206 which suppressed IGF-1 transcription [10]. In Lu L. et al., astragalus polysaccharide (APS) reduced proinflammatory cytokines and regulated oxidative stress, thereby inhibiting muscle loss [35].

In Wang D. et al., the administration of Jian-Pi-Yi-Shen (JPYS) decoction prevented muscle loss, muscle protein degradation, and increased muscle protein synthesis. In addition, JPYS decoction not only inhibited FoxO3a activation and ubiquitin-proteasome system (UPS), but also increased Cox IV, NRF-1, and PGC-1α [25]. Atrogin-1 and MuRF-1 were also measured in the study by Geng Z et al., and astragalus polysaccharide significantly reduced the expression of atrogin-1 and ubiquitin in rat skeletal muscle [38].

In CKD-induced mice, the levels of autophagy-related proteins including Bnip3 and Beclin-1 were increased. Likewise, the ratio of the autophagy proteins LC3II-to-LC3I, associated with autophagosome formation, was increased. Su Z. et al. suggested that using Acu/LFES suppressed the CKD-induced upregulation of autophagy by inhibiting those proteins [26].

(F) Tumor-Induced Model. All the tumor model studies measured markers of the immune system, such as TNF-α and interleukins. In the study by Kim AY et al., Sosiho-tang suppressed the production of cachexia-inflammatory cytokines (IL-6, IL-1, and TNF-α) and these inhibited the activation of nitric oxide and p38, NF-κB, and STAT3, thereby reducing muscle loss [32]. Another study by Kim AY et al., a novel herbal formula, SGE, also decreased inflammatory cytokines [39] and Zhuang et al. found that the Zhimu-Huangbai (1:1) herb pair reduced tumor-induced muscle loss and inhibited cachectic cytokines [8].

(G) Dexamethasone or Alcohol-Induced Model. Kim et al. found a statistically significant inhibition of muscle loss in the dexamethasone-induced muscle atrophy model after treating with Fructus Schisandrae by the activation of SOD, CAT, and GSH [13]. Furthermore, Kim et al. treated with Radix Pueraria extract and Shihosogan-san (SHSGS), both of which inhibited muscular atrophy by inhibiting Bax and promoting Bcl-2 [20, 22].

(H) The Others. In a study by Yuki Kishida et al., Go-sha-jinki-Gan (GJG) was administered to a senescence-accelerated mouse which promoted pAMPK and PGC-1α, thereby activating mitochondrial neogenesis and oxidative metabolism [9].

Yuya Nakashima et al. demonstrated that significant decreases in muscle loss and oxidative stress due to the reduction of malondialdehyde (MDA) and 4-hydroxyalkenals (HAE) of muscle cells occurred after treating with Chlorella extract [11].

In Zhang YT et al., spinal cord injury-induced (SCI) muscular atrophy model was treated with E-AT [29]. E-AT increased the expression levels of choline acetyltransferase (ChAT), which is a transferase enzyme responsible for the synthesis of the excitatory neurotransmitter acetylcholine [50]. Likewise, E-AT increased the protein neurotrophin-3 (NT-3), a member of the neurotrophin family, and has an important role in neuroprotection and axonal regeneration [51]. Through these mechanisms, E-AT on SCI rat protected the motor neurons as well as alleviated muscular atrophy.

In Tseng YT et al. using spinal muscular atrophy rat model, Liuwei dihuang water extract (LWDH-WE) improved muscle strength and body weight accompanied by upregulation of survival motor neuron protein in spinal cord and gastrocnemius muscle tissues [40].

3.3. In Vitro Studies

A total of 17 (8 in vitro only, 9 in vivo with in vitro) articles were classified as in vitro studies in this review.

3.3.1. Muscle Cell Model

C2C12 cells (myoblasts and myotubes) were used in 15 of the 17 studies. There was 1 study using L6 myoblasts and 1 using NSC34 motor neuron-like cells. The TNF-α-induced apoptosis and autophagy model were used in 4 studies, while the oxidative stress model was used in 3 studies. In addition to these, 3 studies utilized the no treatment model, 2 using cancer model. The dexamethasone-treated, PI3K-p110-suppressed, AICAR-treated, starvation-induced, and transgenic models were used in 1 study each (Figure 4).

Figure 4: Muscle cell models of in vitro studies.

3.3.2. Interventions

All 17 studies used herbal medicine as the intervention method. The treatment period spanned 24 hours in 8 studies, 48 hours in 7 studies, and 72 hours in 1 study. One study did not report the treatment period.

3.3.3. Outcomes

Myotube diameter and muscle cell number were set as the primary outcomes. In most studies, significant increases in both the diameter of myotubes and muscle cell numbers were reported (Tables 3 and 4).

Table 4: Summary of articles on complementary and alternative medicine therapies for muscular atrophy (in vitro).

Authors
Design
Origin
Group / Sample-Size (n)
Sample Model
Duration
Outcome Measures
Quantity and Type of Intervention
Main Outcomes

Lu L
2013 [41]
In vitro
China
Control
DEX
DEX + APS
APS
Dexamethasone (DEX) or peroxide-induced atrophy C2C12 cells
24 h
(1) Myotube diameter
(2) Akt/mTOR activation
(3) PTP1B expression and activity
(4) Myoblasts proliferation
(5) Anti-apoptosis
(6) Apoptosis related protein expression
0.2 mg/mL Astragalus polysaccharide (APS)
(1) Muscle fiber diameter: DEX + APS > DEX (p<0.05)
(2) p-Akt↑, p-P70s6k↑, p-mTOR↑, p-rpS6↑ (p<0.05 vs. DEX)
(3) PTP1B expression & activity: DEX > DEX + APS (p<0.05)
(4) Proliferation rate: 50 μg/mL < 0.1 mg/mL < 0.2 mg/mL (p<0.05 vs. Control (Con))
(5) Apoptotic cells: H2O2 > H2O2 + APS (p<0.05)
(6) Caspase-8, Caspase-3: H2O2 > H2O2 + APS
Bcl-2: H2O2 < H2O2 + APS (p<0.05)
Bax: H2O2 > H2O2 + APS (p<0.05)

Jung MH 2010 [42]
In vitro
Korea
Control
H2O2 + IDS 1 μM
H2O2 + IDS 5 μM
H2O2 + IDS 10 μM
H2O2 + IDS 25 μM
H2O2 + NAC 5 mм
C2C12 cell-cultured with H2O2
(0.1, 0.5, 1, 2, 4 mм)
24 h
(1) Antioxidant effects
(2) HSP70 expression
Pre-treatment with Idesolide: cultured for 24 hr with 1, 5, 10, 25 μм idesolide or without idesolide
(1) Cell viability: Con < IDS 1μм < 25 μм < 5 μм < 10 μм (p<0.001 vs. Con)
Con < NAC 5 mм < IDS 25 μм (p<0.001 vs. Con)
(2) HSP70: H2O2 < H2O2 + IDS (p<0.001)

Takeda T 2015 [43]
In vitro
Japan
Control
HJG 1 μg/mL
HJG 10 μg/mL
HJG 50 μg/mL
HJG 100 μg/mL
HJG 200 μg/mL
C2C12 myoblasts (untreated)
3 d
(1) Cell proliferation
(2) ERK1/2 phosphorylation
(3) Akt activity
(4) Differentiation of cells
Hachimijiogan (HJG): 1~200 μg/mL for 3 d
(1) Cell number: HJG (1, 10, 50, 100, 200) > Control (p<0.05)
(2) ERK1/2 activity: HJG200 > Control (2.89 fold, p<0.0001)
(3) Akt activity: Not significant
(4) Cell differentiation: Not significant

Jung MH
2011 [44]
In vitro
Korea
Untreated
H2O2
H2O2 + Sau 10
H2O2 + Sau 25
H2O2 + Sau 50
H2O2 + NAC
H2O2 treated C2C12 cell
24 h
(1) Cell viability
(2) HSP expression
(3) Ceramide content
Sauchinone (Sau): cultured for 24 hr with 10, 25, 50 μM

positive control: N-acetyl cysteine (NAC)
(1) Cell viability: H2O2 + Sau > H2O2 + NAC > H2O2 (p<0.01)
(2) HSP 70 expression: H2O2 + Sau > H2O2 (p<0.01)
(3) Ceramide: H2O2 > H2O2 + Sau (p<0.01)

Chen D
2016 [45]
In vitro
China
Control
TNF-α
TNF-α + ED 5 μM
TNF-α + ED 10 μM
TNF-α + ED 20 μM
TNF-α-induced apoptosis and autophagy C2C12 myoblast
24 h
(1) Anti-apoptosis
(2) Mitochondrial pathway
(3) Autophagy
(4) p-Akt activation
Emodin (ED): component of Rheum palmatum 5, 10, 20 μM
(1) Apoptotic cells: TNF > TNF + ED20 > TNF + ED10 (p<0.05)
(2) Bcl-2/Bax↑, cleaved-caspase 3↓, cleaved-PARP↓ (p<0.05)
(3) LC3↓, Beclin-1↓, Atg7↓ (p<0.05 vs. TNF)
(4) p-Akt↑ (p<0.05 vs. TNF)

Kang YS
2015 [46]
In vitro
Korea
Control
SF 100
SF 200
AICAR
AICAR + SF100
AICAR + SF200
AICAR-induced muscle atrophy C2C12 myotubes
2 d
(1) Myoblast differentiation
(2) Muscle atrophy markers
Schisandrae fructus (SF): Extract of the fruits of Schisandra chinensis Bailon
100, 200 μg/mL
(1) Myosin-heavy-chain↑, Myogenin↑
(2) FoxO3a, MuRF-1. AMPK↓:
AICAR > AICAR + SF100 > AICAR + SF200

Choe YH 2015 [47]
In vitro
Korea
Normal
H2O2
ISO
H2O2 + ISO
H2O2 (1 mM) treated C2C12 cell
24 h
(1) Anti-oxidative stress effect
(2) Anti-apoptosis
(3) ROS marker
(4) Bcl-2, Bax level
(5) Caspase activity
(6) Nrf2/HO-1
Isorhamnetin (ISO):
a flavonoid derived from Hippophae rhamnoides L.
30 μM
(1) Cell viability: H2O2 < H2O2 + ISO
(2) Anti-apoptosis: H2O2 < H2O2 + ISO
(3) ROS: H2O2 > H2O2 + ISO (inhibit 64% vs. H2O2)
(4) Bcl-2↑, Bax↓
(5) Caspase-9, Caspase-3: H2O2 > H2O2 + ISO (p<0.05)
(6) Nrf2↑, HO-1↑

Li F 2017 [48]
In vitro
China
CON
SF
Rg1 10⁻⁴ 
Rg1 10⁻³ 
Rg1 10⁻² 
Rg1 10⁻¹
Starvation induced muscle protein degradation C2C12 myoblast
48h
(1) Atrogin-1 and MuRF-1 expression
(2) PI3K-dependent phosphorylation of AKT, FoxO and mTOR
SF: Serum-free medium for 48h incubation (Starvation induced)
Rg1: Ginsenoside Rg1 10⁻⁴, 10⁻³, 10⁻² and 10⁻¹ mM. incubate for 48h
(1) Atrogin-1: SF > Rg1 10⁻¹ > Rg1 10⁻⁴ > Rg1 10⁻³ > Rg1 10⁻² (p<0.05 vs. SF)
MuRF-1: SF > Rg1 10⁻⁴ > Rg1 10⁻³ > Rg1 10⁻² (p<0.05 vs. SF)
(2) p-FoxO1↑, p-FoxO3a↑, p-Akt↑, p-mTOR↑ (p<0.05)

(A) Oxidative Stress Model. In the three studies using the oxidative stress model, Jung et al. found that idesolide extract protected muscle cells from oxidative stress by promoting the activation of heat shock protein 70 (HSP70) in the cells [42]. HSP70 protects cells from a number of apoptotic stimuli, including oxidative stress and is significantly downregulated in various models of skeletal muscle atrophy [52]. They also found the same effects when sauchinone (root of Saururus chinensis) was used as the mode of treatment [44].

In Choe YH., isorhamnetin (ISO) extract was treated to hydrogen peroxide- (H2O2-) induced oxidation damaged muscle cells. In general, H2O2 causes cell apoptosis with mitochondrial damage and ROS generation by upregulation of Bax and downregulation of Bcl-2 [53]. The ISO extract inhibited the apoptosis by the restoration of Bax, Bcl-2 proteins, and decreasing of caspase-9 and caspase-3. In addition, the ISO activated the antioxidant protein heme oxygenase-1 (HO-1) and its transcription factor, nuclear factor erythroid derived 2-related factor 2 (Nrf2), thereby suppressing oxidative stress [47].

(B) AICAR-Induced Model. Kang et al. found that the administration of Schisandrae Fructus (SF) extract to AICAR (5-aminoimidazole-4-carboxamide-ribonucleotide)-induced muscle atrophy C2C12 myotubes significantly counteracted AICAR-induced muscle cell atrophy and reversed the increased expression of MuRF-1 and FoxO3a [46]. AICAR is an enzyme that upregulates MuRF-1 and stimulates the levels of the FoxO3a transcription factor [54]. SF extract could reverse the muscle cell atrophy caused by AICAR through regulation of the AMPK and FoxO3a signaling pathways, followed by inhibition of MuRF-1.

(C) TNF-α-Induced Model. In Lu L. et al., the ratio of phosphorylated mTOR to total mTOR was decreased, whereas the ratio of LC3B-II to LC3B-I increased after TNF-α treatment. APS restored the downregulation of p-mTOR and increased the ratio of LC3B-II to LC3B-I [35]. In Chen D. et al. using Emodin (ED) to TNF-α treated C2C12 myoblasts, ED significantly attenuated mitochondrial signaling pathways related cell apoptosis by increasing of Bcl-2 and decreasing of Bax, cleaved caspase-3 and cleaved-PARP. In addition, ED inhibited autophagy by suppressing the expression of LC3-II, Beclin-1, and Atg7 [45].

In the study by Cho SG et al., herbal formula consisting of Schisandra chinensis Baill, Lycium chinense Mill, and Eucommiaulmoides Oliv significantly inhibited protein degradation by decreasing atrogin-1 and MuRF-1 and promoted synthesis by stimulating Akt/mTOR signaling pathway. The formula also increased MyoD and myogenin [36]. Geng Z et al. used APS and pyrrolidine dithiocarbamate (PDTC) to TNF-α treated L6 myoblasts. Both extracts delayed muscle cell atrophy through reducing atrogin-1 and ubiquitin [38].

(D) Untreated Model. In the studies using the untreated C2C12 myoblast model, Takeda et al. showed that administration of Hachimijiogan (HJG) to untreated C2C12 cells promoted muscle cell proliferation through activation of ERK1/2 signaling pathway without affecting the Akt signaling pathway [43]. In a study by Sung BK et al., the expression levels of myogenic proteins (MyoD and myogenin) and functional myosin heavy chain (MyHC) were measured to evaluate the myogenic potential of loquat leaf extract (LE). LE enhanced those proteins and also activated the PI3K-Akt/mTOR signaling pathway [34]. In Zhu M. et al., the results indicated that Bu Zhong Yi Qi decoction (BZ) significantly downregulated NCoR1 expression and further induced muscle differentiation and metabolism by regulating NCoR1-associated gene expression [37].

(E) Tumor-Mediated Model. Kim AY et al. found that sosiho-tang decreased serum IL-6 levels and TNF-α [32]. In another study by Kim AY et al., herbal formula, SGE also reduced IL-1β, IL-6, and TNF-α [39].

(F) The Others. In Zhang’s study using PI3K-p110-suppressed C2C12 cells, icaritin extract promoted the expression of PI3K-Akt signaling markers [33].

Lu L. et al. reported in a study using the dexamethasone-induced muscle cell injury model that APS increased p-Akt, p-mTOR, p-P70s6k, and p-rsS6 and inhibited FoxO3a/FoxO1 [41].

In Tseng YT et al., inducible survival motor neuron-knockdown NSC34 motor neuron-like cells were used to mimic survival motor neuron- (SMN-) deficient condition. LWDH-WE significantly increased mitochondrial membrane potential and suppressed apoptosis by attenuating the SMN deficiency-induced downregulation of Bcl-2 and upregulation of cytosolic cytochrome c and cleaved caspase-3 [40].

In Li F et al., starvation-induced muscle protein degradation model by incubation of the cells with serum-free basal medium was treated with ginsenoside Rg1. The Rg1 inhibited MuRF-1 and atrogin-1 and also activated the p-mTOR, Akt, p-FoxO1, and p-FoxO3a [48].

4. Discussion

As the threat of the global aging phenomenon rises, there has been a growing interest in healthy aging, which in turn has led to an increased interest in muscular atrophy and sarcopenia within the medical community.

Recently, many clinical cases, trials, and preclinical studies have been conducted on the effect of CAM on muscular atrophy; however, a review of the study results and treatment mechanisms reported has been inadequate. We performed the review to establish clinical evidence and suggest a direction for future research in finding treatment mechanisms.

As the results showed, the hindlimb suspension and nerve damaged models were most commonly used in the in vivo studies, which are preferred because they can be induced muscle atrophy by directly and mechanically. CKD model, cancer model, stroke model, and diabetes model were useful for studying muscle atrophy that results from comorbidity of several common diseases.

In many studies, to find the mechanisms of action of muscular atrophy treatment, various markers of muscle protein synthesis and muscular atrophy inhibitors were measured.

In the majority of studies including our review, PI3K-Akt-mTOR signaling pathway factors were investigated. The activation of PI3K leads to activation of the serine/threonine kinase Akt, which in turn phosphorylates and activates its downstream proteins (mTOR, p70S6K, 4EBP1, and eIF4E) and resulted in increased protein synthesis and led to skeletal muscle hypertrophy [55, 56]. Mammalian target of rapamycin (mTOR) which is activated by PI3K-Akt signaling pathway functions as a protein kinase that directly influence cell growth and protein synthesis [57]. As the above markers are included in the major pathways in muscular atrophy, these are suggested to be measured in the related studies.

In addition, other cell proliferation pathway proteins like TRPV4, ERK1/2 could be investigated. TRPV4, a member of the TRP channel superfamily, is known to promote physiological functions in muscle [58], and ERK1/2 is member of the mitogen-activated protein kinase super family that can mediate cell proliferation and apoptosis in the Ras–Raf–MEK–ERK signaling cascade [59].

MuRF1 and FoxO3/atrogin-1 are proteins leading to upregulation of the UPS pathway to catalyze the myofibrillar proteins [60]. FoxO3 can be phosphorylated by Akt, and deactivation of Akt would lead to relocation of FoxO into the nucleus and activate atrophy-induced genes. Activated FoxO3 stimulates lysosomal proteolysis in muscle by activating the autophagy process by transcriptional regulation [61]. So, these proteins are needed to find the activation of UPS pathway in muscle atrophy.

In the cell apoptotic markers, Bax, a proapoptotic factor that promotes cell death, and Bcl-2, an antiapoptotic factor, were mainly used. Caspase-9 and caspase-3 were also measured because they were the key caspase proteases in the activation of intrinsic apoptosis pathway [62]. Through the measurement of those apoptotic factors, the efficacy of suppressing muscle cell apoptosis can be verified.

MyoD, MHC-II, MyHC, and myogenin were measured to investigate the level of myogenesis. MyoD, MHC-II, and MyHC are proteins that play a major role in regulating muscle differentiation, and myogenin is a transcription factor involved in coordination of skeletal muscle development or myogenesis and repair.

Mitochondria related proteins like PGC-1α, Cox IV, and NRF-1 were measured to investigate the effect of skeletal muscle metabolism through modulating mitochondrial biogenesis. Also, NCoR1 were measured as a key modulator of the mitochondrial metabolism in muscle, which can reprogram muscle metabolism from a glycolytic to a more oxidative mitochondrial state [63].

In this literature review, we searched for articles on CAM as a treatment modality for muscular atrophy. However, owing to the small number of studies used in the review, only a qualitative analysis of the data could be done. Further studies must be carried out to provide additional evidence to support our findings.

5. Conclusion

In this study, outcome measures of muscle mass and function were used to evaluate the effects of complementary and alternative medicine on muscular atrophy and, in most of studies, the results have proven it to be significantly effective. Markers of muscle protein synthesis and muscle atrophy inhibitors were measured to find their treatment mechanisms. In those mechanisms, (1) changes in growth hormone/IGF productivity and sensitivity by aging, (2) decrease of muscle protein by proinflammatory cytokines (TNF-α, IL-1, IL-6, etc.), (3) acceleration of apoptosis in muscle cells, (4) ubiquitin-proteasome proteolytic pathway, and (5) Akt/mTOR signaling pathway were found to be important factors contributing to treatment effects.

In most of the studies we have investigated, CAM promoted protein synthesis and inhibited degradation by enhancing the PI3K-Akt-mTOR signaling pathway. It also inhibited the ubiquitin-proteasome system which was involved in protein degradation. In several studies, CAM alleviated skeletal muscle metabolism through modulating mitochondrial biogenesis factors, thereby preventing muscle loss. In addition, CAM restored the expression of proteins involved in the cell apoptotic pathway and autophagy pathway in the various models of muscular atrophy.

Conflicts of Interest

The authors declare that there are no conflicts of interest regarding the publication of this paper.

Authors’ Contributions

Yong-Hyeon Baek is responsible for developing the research strategy and data extraction form, supervising the research fulfillment, and drafting the manuscript. Byung-Kwan Seo contributed to developing the research strategy and drafting the manuscript. Seong-Mok Jeong is responsible for searching articles, developing data extraction form, extracting data, and drafting the manuscript. Yeon-Cheol Park contributed to analyzing articles and extracting data. All authors have read, revised, and approved the final manuscript. Seong-Mok Jeong and Byung-Kwan Seo contributed equally to this work.

Acknowledgments

This research was supported by the Basic Science Research Program, through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (NRF-2016R1D1A1B03930503).

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