Does Exercise Regulate Autophagy in Humans? A Systematic Review and Meta-Analysis

Figures & data

Table 1. Characteristics of available evidence on autophagic responses to exercise in humans.

Source	Participants’ Characteristic	Physical Exercise	Sample	Autophagic Response
Arribat et al., 2018	Healthy sedentary (n = 22, male = 11, age = 66.2 ± 3.8 yr) and lifelong trained adults (n = 8, male = 4, age = 65.6 ± 6.7 yr)	Long-term (16 weeks); cycling, treadmill walking/running, and outdoor walking; endurance exercise, average of 145 ± 33 min/week	Muscle	PINK1↑; BNIP3↑; VDAC1→; PARKIN→; BCL2L13→; SQSTM1→; LC3-II→
Botella et al., 2022	Healthy adults (n = 24, male = 24, age = 27.5 ± 7.7/22.4 ± 5.2/30.0 ± 7.3 yr)	An acute bout and long-term (20 days); cycling; An acute bout: 82%, 94%, and 106% maximal lactate steady state, 6 sessions of peak power with 4 min intervals, 90 min of continuous exercise at 42% peak power; Long-term: 7–10 sessions of HIIT at peak power with 4 min intervals at 50% power output, twice a day	Muscle	LC3⇢⇣↑, SQSTM1⇢→
Brandt et al., 2018	Physically active adults (n = 12, male = 12, age = 19-33 yr)	An acute bout and Long-term (8 weeks); cycling; moderate: 60 min at 157 ± 20 W, 3 days/week; sprint: 60 min at 157 ± 20 W and 6 sets of 30s sprints at 473 ± 102 W + 3.24 min at 102 ± 17 W, 3 days/week	Muscle	ULK1^S317⇡; SQSTM1⇢→; BECN1⇡↑^m→^s; BNIP3⇡↑; PARKIN⇢↑; LC3-II⇡→
Brinkmann et al., 2017	Type 2 diabetic adults (n = 8, male = 8, age = 61 ± 10 yr)	Long-term (12 weeks); cycling and elliptical cross-trainer; 5 min warm-up + (20 min in week 1 to 50 min in week 7 at 70–80% of HRpeak) + 5min cool-down, 3 times/week	Muscle	BNIP3→; LC3-II→
Dokladny et al., 2013	Endurance-trained adults (n = 8, male = NA, age = 18–45 yr)	An acute bout; treadmill running; 60 min at 70–80% of VO2 max	PBMC	LC3-II⇡
Escobar et al., 2021	Physically active adults (n = 10, male = 5, age = 25.2 ± 1.1 (male) or 21.6 ± 3.6 (female) yr)	An acute bout; treadmill running; HIIT: 2 min warm-up + 12 bouts of 1 min at 100% of Vmax followed by 1 min at 3 mph (interval) + 2 min cool-down; MICT: 2 min warm-up + 60 min at 55% Vmax and 3% grade + 2 min cool-down	Muscle & PBMC	SQSTM1⇡(muscle) & ⇢(PBMC); LC3-II⇡^h⇣^m (PBMC) & ⇢(muscle)
Fiorenza et al., 2019	Essential hypertensive (n = 24, male = 24, age = 60.8 ± 1.5 yr) and normotensive adults (n = 13, male = 13, age = 58.4 ± 2.5 yr)	Long-term (6 weeks); cycling; HIIT: 7 min warm‐up + (2 × 5 bouts in week 1 & 2 to 3 × 5 bouts in week 3–6 five consecutive 1 min cycling (10s, 20s, and 30s at 30%, 50%, and 100% maximal intensity, respectively) with 3 min of recovery (interval)	Muscle	SQSTM1↑; LC3-II↑(normotensive) & →(hypertensive)
Fritzen et al., 2016	Healthy moderately trained (n = 7, male = 7, age: 27 ± 2 yr) and untrained adults (n = 8, male = 8, age = 25 ± 1 yr)	An acute bout and Long-term (3 week); one-legged knee extensor exercise; An acute bout: 60 min at 80% PWL with two 5 min intervals at 100% PWL; Long-term: 4, 5, and 6 sessions in week 1, 2, and 3, respectively, with duration increased from 1 to 2 h per session at intensity between 70-85% PWL	Muscle	SQSTM1⇢→; ULK1^S555⇢; LC3-II⇣→
Fry et al., 2013	Young (n = 16, male = 8, age: 27 ± 8 yr) and old adults (n = 16, male = 8, age = 70 ± 8 yr)	An acute bout; resistance exercise; warm-up: 10 repetitions at 45% RM) + 8 sets of 10 repetitions at 70% RM with 3 min of rest interval	Muscle	ATG7⇡ (old) & ⇢(young); BECN⇢; LC3-II⇣
Glynn et al., 2010	Healthy adults (n = 13, male = 13, age = 30 ± 5.3/32 ± 2.4 yr)	An acute bout; resistance exercise (bilateral leg extension); warm-up (23 kg × 10 repetitions) + 10 sets of 10 repetitions at 70% RM with 3 min of rest interval	Muscle	LC3-II⇢
Hentil€a et al., 2018	Healthy untrained young (n = 12, male = 12, age: 27 ± 4 yr) and old (n = 8, male = 8, age: 61 ± 6 yr) adults & trained young adults (n = 15, male = 10, age = 25 ± 5 yr)	An acute bout and Long-term (21 weeks); resistance exercise (leg press device); Acute: 5 × 10 RM or 4 × 10 RM with 1 min of rest interval; Long-term: 5 × 10 RM per session, 2 sessions/week	Muscle	ULK1^S757⇢↑; ULK1^S555⇣↓; BECN⇢→; SQSTM1⇡→; LC3-II⇣⇡^#↑
Hentil€a et al., 2020	Competitive sprinter (n = 32, male = 32, age = 40-76 yr)	Long-term (20 weeks); resistance exercise (heavy and explosive strength); 1^st phase: heavy (3–4 sets × 8-12 repetitions, 50%–70% of RM), 2^nd & 3^rd phase: heavy (2–3 sets × 4–6 repetitions, 70%–85% of RM) + explosive (2–3 sets × 4–6 repetitions, 35%–60% of RM) + mixed (2–3 sets × 3–10 repetitions)	PBMC	ULK1^S757→; BECN→; SQSTM1↓; LC3-II↑
Huang et al., 2019	Obese (n = 6, male = 6, age: 27.72 ± 2.41 yr) and normal-weight (n = 6, male = 6, age = 24.76 ± 1.52 yr) adults	An acute bout; treadmill running; 3 min warm-up at 60% HRmax + increase in speed until 80% of HRmax & increase in grade by 2%/2 min until attainment of VO2max	PBMC	LC3-II⇡⇣^#
Jamart et al., 2012	Athletes (n = 11, male = 11, age = 42.1 ± 7.8 yr)	An acute bout; treadmill running; 24-h protocol with a freely chosen speed and rest interval every 4 hour	Muscle	ATG3⇢; ATG7⇢; ATG12⇡; BECN⇢; BNIP3⇢; PARKIN⇢; PINK1⇢; LC3-II⇡
Kröpfl et al., 2022	Healthy adults (n = 8, male = NA, age = NA)	An acute bout; cycling; warm-up at 50 W and followed by increase of 20/30 w/min	PBMC	SQSTM1⇢; LC3-II⇢
Kruse et al., 2017	Type 2 diabetic (n = 13, male = 13, age: 55.4 ± 7.2 yr) and non-diabetic (n = 14, male = 14, age = 54.7 ± 8.6 yr) adults	An acute bout; cycling; 60 min at 70% of VO2max	Muscle	ULK1^S555⇡; ULK1^S757⇣; ULK1⇢; BNIP3⇢; ATG7⇡; SQSTM1⇡; LC3-II⇣
Masschelein et al., 2014	Monozygotic twins (n = 22, male = NA, age = 24.4 ± 3.8 yr)	An acute bout; cycling; 20 min submaximal constant-load (about 50 % of VO2max)	Muscle	ATG12⇢; BNIP3⇢; SQSTM1⇢; LC3-II⇢
Mazo et al., 2021	Healthy untrained adults (n = 6, male = 6, age = 27 ± 7.3 yr)	An acute bout; aerobic: 40 min cycling at 75% HRpeak; Resistance: 8 set of 10 repetitions of isotonic unilateral leg extensions at 60-65% unilateral RM	Muscle	SQSTM1⇣; LC3-II⇣
McCormick et al., 2019	Pre-diabetes (n = 6, male = 3, age = 42.4 ± 11.7 yr) and healthy (n = 6, male = 3, age = 44.4 ± 11.9 yr) adults	An acute bout; cycling; 5 min warm-up at 20% VO2max + 60 min at 50% of VO2max (3 sets of 20 min separated by 5 min interval)	PBMC	SQSTM1⇢; LC3-II⇡(healthy) & ⇢(prediabetes)
Mejías-Peña et al., 2016	Healthy old (n = 29, male = 8, age = 69.7 ± 5.4 yr) and young (n = 15, male = 7, age = 20.6 ± 3.1 yr) adults	Long-term (8 weeks); cycling; 5 min warm-up + 15–20 min at 70–75 % HRmax + 5 min cool-down, 2 sessions/week	PBMC	ULK1^S757↓; ATG12↑; ATG16↑; BECN↑; LAMP2→; SQSTM1↓; LC3-II/LC3-I↑
Mejías-Peña et al., 2017	Healthy old adults (n = 26, male = 7, age = 65-78 yr)	Long-term (8 weeks); resistance exercise; 10 min warm-up + 3 × 8 to 3 × 12 at 60% to 80% RM from week 1 to week 8, 2 sessions/week	PBMC	ULK1^S757↓; ATG12↑; ATG16↑; BECN↑; LAMP2↑; SQSTM1↓; LC3-II/LC3-I→
Moberg et al., 2017	Healthy soldiers (n = 24, male = 17, age = 19-34 yr)	An acute bout; mixed type exercise; 8 days physical activity in varying terrain or moving soldiers carried gear (35 kg)	Muscle	ULK1^S317⇡; ULK1^S555⇡; ULK1^S638⇢; ULK1⇡; BECN⇢; SQSTM1⇢; LC3-II⇡
Moberg et al., 2022	Healthy adults (n = 8, male = 8, age = 31 ± 2 yr)	An acute bout; resistance exercise; 8-10 repetitions of leg extensions at 70% 1RM with a 3-min interval at 0% 1RM	Muscle	ULK1^S317⇡; GABARAP⇢; BNIP3⇣; LC3-II⇣
Schwalm et al., 2015	Athletes (n = 23, male = 23, age = 22/23/24 ± 2.6 yr)	An acute bout; cycling; low-intensity: 2 h at 55% of VO2max; high-intensity: 2 h at 70% VO2max	Muscle	ULK1^S757⇣; ULK1^S317⇡; SQSTM1⇢ (low) & ⇣ (high); LC3B⇣
Schwalm et al., 2017	Athletes (n = 7, male = 7, age = 24 ± 2.6 yr)	An acute bout; cycling; 2 h at 70% VO2max	Muscle	PARKIN⇢; BNIP3⇢; SQSTM1⇢; LC3-II⇢
Tachtsi et al., 2016	Healthy untrained adults (n = 16, male = 16, age = 21.3 ± 4.0 yr)	Acute bout; cycling; 60min at 70% VO2max	Muscle	ULK1⇢; ATG5⇣; PARKIN⇢; PINK1⇢; SQSTM1⇢; LC3-II⇢
Ulbricht et al., 2015	Moderately trained adults (n = 17, male = 17, age = 25 ± 8.2 yr)	Acute bout and Long-term (4 weeks); resistance exercise (leg extension); Acute bout: 3 sets of 8 repetitions at 100% maximum eccentric force with 3 min interval; Long-term (constant load): 6 sets (3 sets extension + 3 sets press with 2 min interval) of 8–12 repetitions at 75–80% maximum eccentric force; Long-term (progressive load): repetition intensity increase at 5%	Muscle	SQSTM1→(constant) & ↑(progressive); LC3-II⇡

Abbreviations: Muscle = skeletal muscle; HIIT = high intensity interval training; HRmax = maximal heart rate; HR_peak = peak heart rate; MICT = moderate-intensity continuous training; mph = mile per hour; PWL = peak work load; RM = repetition maximum; V_max = maximal velocity; VO_2max = maximal oxygen consumption; ⇢ = unchanged, ⇡ = increase, ⇣ = decrease after an acute bout of exercise; → = unchanged, ↑ = increase, and ↓ = decrease after long-term exercise; #, differ between post-exercise time points; NA, not available

Figure 1. The effect of exercise modality on the levels of LC3-II in humans following exercise. (A): Acute bout of moderate-intensity endurance exercise. (B): Acute bout of vigorous-intensity endurance exercise. (C): Acute bout of resistance exercise. (D): Long-term moderate-intensity endurance exercise. (E): Long-term vigorous-intensity endurance exercise. (F): Long-term resistance exercise. CI: Confidence interval; MD: mean difference.

Figure 2. The effect of exercise modality on the levels of SQSTM1 in humans following exercise. (A): Acute bout of moderate-intensity endurance exercise. (B): Acute bout of vigorous-intensity endurance exercise. (C): Acute bout of resistance exercise. (D): Long-term moderate-intensity endurance exercise. (E): Long-term vigorous-intensity endurance exercise. (F): Long-term resistance exercise. CI: Confidence interval; MD: mean difference.

Figure 3. The effect of tissue type on the levels of LC3-II in humans following exercise. (A): Skeletal muscles. (B): Peripheral blood mononuclear cells (PBMCs). (C): The effect of resistance exercise on LC3-II levels in skeletal muscles. CI: Confidence interval; MD: mean difference.

Figure 4. The effect of tissue type on the levels of SQSTM1 in humans following exercise. (A): Skeletal muscles. (B): Peripheral blood mononuclear cells (PBMCs). CI: Confidence interval; MD: mean difference.

Figure 5. The effect of exercise on the levels of ULK1, ATG12, and BECN1 in humans. (A): Unc-51 like autophagy activating kinase (ULK1)^S317. (B): ULK1^S555. (C): ULK1^S757. (D): Autophagy-related gene (ATG)12. (E): Beclin1 (BECN1). CI: Confidence interval; MD: mean difference.

Figure 6. The effect of exercise on the levels of BNIP3 and PARKIN in humans. (A): BCL2/adenovirus E1B 19 kDa protein-interacting protein 3 (BNIP3). (B): PARKIN. CI: Confidence interval; MD: mean difference.

Figure 7. Schematic overview of autophagic responses to exercise in humans.