. 2021 Mar 1;25(2):181–206. doi: 10.1007/s40291-020-00510-6

Table 6.

Summary of exercise training studies in mitochondrial disease.

Exercise training intervention	Disease(s)/syndrome(s) investigated	Study design	N, gender and age; mean ± SD (range)	Most recent publication	Results	References
3d·wk⁻¹ for 16 wks; cycle ergometer; 70–80% VO₂max; 30 min	m.3243A>G pathogenic variant (n = 10) Exercise intolerance (n = 10)	SGT+ HCs	10 6M/4F; 39 ± 11·8	2015	Increased VO₂peak (mL/min, mL/kg/min, % predicted) Peak power Peak a-vO₂ difference (mL/dL) VO₂ at VAT (mL/min/kg) Left ventricular mass and left ventricular mass index	[135] [140]
~4d·wk^-1 for 12 wks; stationary bike; 65–75% VO₂max; 30 min	m.3243A>G pathogenic variant (n = 13), single large-scale deletions (n = 5), 8344 A>G pathogenic variant (n = 1), ND2 microdeletion (n = 1) Exercise intolerance (n = 14)	SGT + HCs	20 10M/10F; 41 ± 12 (26–57)	2006	Increased VO₂peak (mL/kg/min) Peak power Citrate synthase activity Ratio between mDNA and nDNA Self-reported walking distance Self-reported muscle strength Self-reported endurance Self-reported physical activity Decreased Capillary density Fatigue	[134]
5d·wk^-1 for 12 wks; stationary bike; 70% VO₂max; 30 min 3–12 months of deconditioning prior to long-term study: 3d·wk^-1 for 12 months (n = 3); 6 months (n = 1)	m.3243A>G pathogenic variant (n = 1), single large-scale deletions (n = 1), 8344 A>G pathogenic variant (n = 1), ND2 microdeletion (n = 1) Exercise intolerance (n = 4). Patients in prior study ³	SGT	4 4M; 31·8 ± 4 (27–36)	2009	Increased VO₂peak (mL/kg/min) Peak power Citrate synthase activity (12 wks only) Type I fibre area (6 months only) Capillary density (12 months only) Self-reported muscle strength Self-reported endurance	[141]
4d·wk^-1 for 12 wks; cycle ergometer; 65–70% HRmax; 30 min for 1st 6 wks, 45 min thereafter (split into 15 or 30 min)	Metabolic myopathy (n = 6). Varied from no functional impairment to significant exercise intolerance.	SGT	6 4M/2F; 51 ± 16	2016	Increased VO₂peak (L/min, mL/kg/min) and ↑ VCO₂ peak (L/min) Peak power Peak stroke volume Cardiac output Muscle oxygenation index obtained by near-infrared spectroscopy (NIRS) Constant work rate exercise test (50% pre-training maximal workload): Decreased Peak rate of perceived exertion (RPE) Constant work rate exercise test (50% pre-training maximal workload): Decreased VO₂ (L/min, mL/kg/min) VE HR Cardiac output RPE O₂ cost of cycling (mL·min^-1·watt^-1)	[139]
~3–4d·wk^-1 for 10 wks; cycle ergometer; Constant near-lactate threshold workload: ≤ 70 HRmax; 30 min for 1st 5 wks, 45 min (with 5-min rest halfway), thereafter	Single large-scale deletions (n = 6), multiple deletions (n = 3), A5814G mtDNA point pathogenic variant (n = 1), pathogenic variant unknown (n = 2) Mitochondrial myopathy (n = 12)	SGT + HCs	12 1M/11F; 46·7 ± 5·6 SE	1999	Increased QoL (SF-36) Decreased Peak blood lactate during constant near-lactate threshold workload test	[142]
Single large-scale deletions (n = 4), multiple deletions (n = 3) Mitochondrial myopathy (n = 7)	SGT	7 1M/6F; 44·9 ± 12·1 (28–62)	2012 24	Decreased Resting plasma lipoperoxide	[150]
3–4d·wk^-1 for 8 wks; treadmill walking; 60–80% HRR; 20- to 30-min (bouts if required for ~1st 4 wks with rest: time taken for HR to ↓ within 10% pre-HR)	mtDNA deletion (n = 5), 8344 A>G pathogenic variant (n = 1), tRNA(Leu (CUN)) pathogenic variant (n = 1), Unknown pathogenic variants (n = 3) Exercise intolerance (n = 10), muscle weakness (n = 10), mitochondrial myopathy (n = 6), lactic acidosis (n = 8)	SGT	10 4M/6F; 36 ± 9 (25–58)	1998	Increased Exercise duration QoL (SF-36: Physical component summary) Decreased Resting HR Resting blood lactate ADP recovery half-time Submaximal exercise test (80% predicted HRmax): Increased Aerobic capacity (METS) Decreased Blood lactate at 70% pre-training predicted HRmax HR	[136]
3–4d·wk^-1 for 8 wks; treadmill walking; 70–85% HRR; 20- to 30-min	10 patients in prior study ⁴. Additional 4 patients: mtDNA deletion. Mitochondrial myopathy (n = 3)	SGT + HCs	14 4M/10F; 36·4 ± 9·8 (14–58)	1999	Increased QoL (SF-36) Decreased Resting blood lactate ADP recovery half time Submaximal exercise test (85% predicted HRR): Increased Aerobic capacity (METS) Decreased Blood lactate at 70% pre-training predicted HR	[143]
3–4d·wk^-1 for 14 weeks; cycle ergometer; 70–80% HRmax; 30- to 40-min (30 min for the 1st 7 weeks, 40 min thereafter)	Unidentified (n = 1), TRNAGlu (n = 1), TrpT5543C pathogenic variant (n = 1), ND4 pathogenic variant (n = 1), G5920A pathogenic variant (n = 1), G14846A pathogenic variant (n = 1), cytochrome b deletion (n = 1), single, large-scale deletions (n = 2), 15-bp Microdeletion COX subunit III (n = 1)* Exercise intolerance (n = 10)	SGT	10 4M/6F; 39·3 ± 9·5 (24–53) n = 8*	2007	Increased VO₂peak (mL/kg/min) Peak power Peak a-vO₂ difference (mL/dL) Initial rate of PCr resynthesis (V) Apparent maximum rate of oxidative ATP synthesis (Qmax) Citrate synthase activity Complex II activity Complex IV activity Mutant mtDNA relative to total mtDNA (%) Cytochrome c protein mtHSP70 protein MnSOD protein Bax protein Decreased Resting HR HR at 70–80% pre-training maximal workload Peak blood lactate Whole muscle aconitase activity/mU mitochondria (Complex IV) OGG-1 protein	[132]
3–4d·wk^-1 for 14 wks* (3·wk^-1 for the 1st 7 wks, 4d·wk^-1 thereafter); cycle ergometer; 70–80% HRmax; 30 min for the 1st 7 wks, 40 min thereafter *Randomised to continue until 28 wks (n = 4) or cease (n = 4)	Single large-scale deletions (n = 8). Exercise intolerance to a varying degree (mild to severe) (n = 8)	SGT	8 3M/5F; 40·8 ± 9·7 (25–60)	2006	Increased VO₂peak (L/min) Peak power Peak a-vO₂ difference (mL/dL) QoL (SF-36: Physical component summary) Submaximal constant work rate exercise test (60% HRmax) Decreased RPE HR Blood lactate	[137]
3d·wk^-1 for 12 wks; cycle ergometer; 70–80% HRmax; 30 min	m.3243A>G pathogenic variant (n = 5), Ragged-red fibers (n = 5) Muscle weakness or mitochondrial myopathy (n = 10)	SGT	10 3M/7F; 42 ± 14 (20–64)	2006	Increased O₂ extraction (↓ O₂ uptake efficiency slope, i.e. index of cardiorespiratory functional reserve) Peak power Initial rate of PCr resynthesis (V) Apparent maximum rate of oxidative ATP synthesis (Qmax) 6MWT distance Quadriceps whole muscle volume (dm3) Quadriceps whole muscle cross-sectional area	[141]
3d·wk^-1 for 12 wks. Bilateral leg extensors and leg press (3 x 6–8 reps, 80–85% 1-RM, full recovery between sets)	Single large-scale deletions (n = 8) Exercise intolerance to a varying degree (mild to severe) (n = 8)	SGT	8 8F; 38·6 ± 7 (25–48)	2008	Increased 1-RM knee extension 1-RM leg press Peak a-vO₂ difference (mL/dL) nMHC fibres (%) Centrally nucleated fibres (%) NCAM positive fibres (%) Decreased COX-deficient fibres (%)	[137]
3d·wk^-1 for 12 wks. Aerobic training: cycle ergometer; 70% peak work rate; 30 min Strength training: dynamic isotonic shoulder press, butterfly, biceps curls; 1 × 10–15 reps in 1st 2 wks, 2–3 sets thereafter); 50% 1-RM; ~20 min	Exercise intolerance (n = 7), muscle weakness or mitochondrial myopathy (n = 2)	RCT (parallel)	9 5M/4F; 44·8 ± 8 (35–57)	2005	Increased 1-RM butterfly (pectoralis major) 1-RM shoulder press VO₂peak (L/min, % predicted) VAT (% predicted) Peak O₂ pulse (% predicted) HRmax (% predicted) RER/power slope Peak VE Peak breathing frequency Maximum expiratory pressure Maximum inspiratory pressure Submaximal constant work rate exercise test (70% pre-training maximal workload): Increased Time and distance until exhaustion	[138]

Exercise training intervention

Disease(s)/syndrome(s) investigated

Study design

N, gender and age; mean ± SD (range)

Most recent publication

Results

References

3d·wk⁻¹ for 16 wks;

cycle ergometer;

70–80% VO₂max;

30 min

m.3243A>G pathogenic variant (n = 10)

Exercise intolerance (n = 10)

SGT+ HCs

6M/4F;

39 ± 11·8

2015

Increased

VO₂peak (mL/min, mL/kg/min, % predicted)

Peak power

Peak a-vO₂ difference (mL/dL)

VO₂ at VAT (mL/min/kg)

Left ventricular mass and left ventricular mass index

[135]

[140]

~4d·wk^-1 for 12 wks;

stationary bike;

65–75% VO₂max;

30 min

m.3243A>G pathogenic variant (n = 13), single large-scale deletions (n = 5), 8344 A>G pathogenic variant (n = 1), ND2 microdeletion (n = 1)

Exercise intolerance (n = 14)

SGT + HCs

10M/10F;

41 ± 12 (26–57)

2006

Increased

VO₂peak (mL/kg/min)

Peak power

Citrate synthase activity

Ratio between mDNA and nDNA

Self-reported walking distance

Self-reported muscle strength

Self-reported endurance

Self-reported physical activity

Decreased

Capillary density

Fatigue

[134]

5d·wk^-1 for 12 wks;

stationary bike;

70% VO₂max;

30 min

3–12 months of deconditioning prior to long-term study: 3d·wk^-1 for 12 months (n = 3); 6 months (n = 1)

m.3243A>G pathogenic variant (n = 1), single large-scale deletions (n = 1), 8344 A>G pathogenic variant (n = 1), ND2 microdeletion (n = 1)

Exercise intolerance (n = 4).

Patients in prior study ³

SGT

4M;

31·8 ± 4 (27–36)

2009

Increased

VO₂peak (mL/kg/min)

Peak power

Citrate synthase activity (12 wks only)

Type I fibre area (6 months only)

Capillary density (12 months only)

Self-reported muscle strength

Self-reported endurance

[141]

4d·wk^-1 for 12 wks;

cycle ergometer;

65–70% HRmax;

30 min for 1st 6 wks, 45 min thereafter (split into 15 or 30 min)

Metabolic myopathy (n = 6).

Varied from no functional impairment to significant exercise intolerance.

SGT

4M/2F;

51 ± 16

2016

Increased

VO₂peak (L/min, mL/kg/min) and ↑ VCO₂ peak (L/min)

Peak power

Peak stroke volume

Cardiac output

Muscle oxygenation index obtained by near-infrared spectroscopy (NIRS)

Constant work rate exercise test (50% pre-training maximal workload):

Decreased

Peak rate of perceived exertion (RPE)

Constant work rate exercise test (50% pre-training maximal workload):

Decreased

VO₂ (L/min, mL/kg/min)

Cardiac output

RPE

O₂ cost of cycling (mL·min^-1·watt^-1)

[139]

~3–4d·wk^-1 for 10 wks;

cycle ergometer;

Constant near-lactate threshold workload: ≤ 70 HRmax;

30 min for 1st 5 wks, 45 min (with 5-min rest halfway), thereafter

Single large-scale deletions (n = 6), multiple deletions (n = 3), A5814G mtDNA point pathogenic variant (n = 1), pathogenic variant unknown (n = 2)

Mitochondrial myopathy (n = 12)

SGT

+ HCs

1M/11F;

46·7 ± 5·6 SE

1999

Increased

QoL (SF-36)

Decreased

Peak blood lactate during constant near-lactate threshold workload test

[142]

Single large-scale deletions (n = 4), multiple deletions (n = 3)

Mitochondrial myopathy (n = 7)

SGT

1M/6F;

44·9 ± 12·1 (28–62)

2012

Decreased

Resting plasma lipoperoxide

[150]

3–4d·wk^-1 for 8 wks;

treadmill walking;

60–80% HRR;

20- to 30-min (bouts if required for ~1st 4 wks with rest: time taken for HR to ↓ within 10% pre-HR)

mtDNA deletion (n = 5), 8344 A>G pathogenic variant (n = 1), tRNA(Leu (CUN)) pathogenic variant (n = 1), Unknown pathogenic variants (n = 3)

Exercise intolerance (n = 10), muscle weakness (n = 10), mitochondrial myopathy (n = 6), lactic acidosis (n = 8)

SGT

4M/6F;

36 ± 9 (25–58)

1998

Increased

Exercise duration

QoL (SF-36: Physical component summary)

Decreased

Resting HR

Resting blood lactate

ADP recovery half-time

Submaximal exercise test (80% predicted HRmax):

Increased

Aerobic capacity (METS)

Decreased

Blood lactate at 70% pre-training predicted HRmax

[136]

3–4d·wk^-1 for 8 wks;

treadmill walking;

70–85% HRR;

20- to 30-min

10 patients in prior study ⁴.

Additional 4 patients: mtDNA deletion. Mitochondrial myopathy (n = 3)

SGT

+ HCs

4M/10F;

36·4 ± 9·8 (14–58)

1999

Increased

QoL (SF-36)

Decreased

Resting blood lactate

ADP recovery half time

Submaximal exercise test (85% predicted HRR):

Increased

Aerobic capacity (METS)

Decreased

Blood lactate at 70% pre-training predicted

[143]

3–4d·wk^-1 for 14 weeks;

cycle ergometer;

70–80% HRmax;

30- to 40-min (30 min for the 1st 7 weeks, 40 min thereafter)

Unidentified (n = 1),

TRNAGlu (n = 1),

TrpT5543C pathogenic variant (n = 1)*,

ND4 pathogenic variant (n = 1)*,

G5920A pathogenic variant (n = 1)*,

G14846A pathogenic variant (n = 1)*,

cytochrome b deletion (n = 1)*,

single, large-scale deletions (n = 2)*,

15-bp Microdeletion COX subunit III (n = 1)*

Exercise intolerance (n = 10)

SGT

4M/6F;

39·3 ± 9·5 (24–53)

n = 8*

2007

Increased

VO₂peak (mL/kg/min)

Peak power

Peak a-vO₂ difference (mL/dL)

Initial rate of PCr resynthesis (V)

Apparent maximum rate of oxidative ATP synthesis (Qmax)

Citrate synthase activity

Complex II activity

Complex IV activity

Mutant mtDNA relative to total mtDNA (%)

Cytochrome c protein

mtHSP70 protein

MnSOD protein

Bax protein

Decreased

Resting HR

HR at 70–80% pre-training maximal workload

Peak blood lactate

Whole muscle aconitase activity/mU mitochondria (Complex IV)

OGG-1 protein

[132]

3–4d·wk^-1 for 14 wks* (3·wk^-1 for the 1st 7 wks, 4d·wk^-1 thereafter);

cycle ergometer;

70–80% HRmax;

30 min for the 1st 7 wks, 40 min thereafter

*Randomised to continue until 28 wks (n = 4) or cease (n = 4)

Single large-scale deletions (n = 8).

Exercise intolerance to a varying degree (mild to severe) (n = 8)

SGT

3M/5F;

40·8 ± 9·7 (25–60)

2006

Increased

VO₂peak (L/min)

Peak power

Peak a-vO₂ difference (mL/dL)

QoL (SF-36: Physical component summary)

Submaximal constant work rate exercise test (60% HRmax)

Decreased

RPE

Blood lactate

[137]

3d·wk^-1 for 12 wks;

cycle ergometer;

70–80% HRmax;

30 min

m.3243A>G pathogenic variant (n = 5), Ragged-red fibers (n = 5)

Muscle weakness or mitochondrial myopathy (n = 10)

SGT

3M/7F;

42 ± 14 (20–64)

2006

Increased

O₂ extraction (↓ O₂ uptake efficiency slope, i.e. index of cardiorespiratory functional reserve)

Peak power

Initial rate of PCr resynthesis (V)

Apparent maximum rate of oxidative ATP synthesis (Qmax)

6MWT distance

Quadriceps whole muscle volume (dm3)

Quadriceps whole muscle cross-sectional area

[141]

3d·wk^-1 for 12 wks.

Bilateral leg extensors and leg press (3 x 6–8 reps, 80–85% 1-RM, full recovery between sets)

Single large-scale deletions (n = 8)

Exercise intolerance to a varying degree (mild to severe) (n = 8)

SGT

8F; 38·6 ± 7 (25–48)

2008

Increased

1-RM knee extension

1-RM leg press

Peak a-vO₂ difference (mL/dL)

nMHC fibres (%)

Centrally nucleated fibres (%)

NCAM positive fibres (%)

Decreased

COX-deficient fibres (%)

[137]

3d·wk^-1 for 12 wks.

Aerobic training:

cycle ergometer;

70% peak work rate;

30 min

Strength training: dynamic isotonic shoulder press, butterfly, biceps curls; 1 × 10–15 reps in 1st 2 wks, 2–3 sets thereafter); 50% 1-RM;

~20 min

Exercise intolerance (n = 7), muscle weakness or mitochondrial myopathy (n = 2)

RCT (parallel)

5M/4F;

44·8 ± 8 (35–57)

2005

Increased

1-RM butterfly (pectoralis major)

1-RM shoulder press

VO₂peak (L/min, % predicted)

VAT (% predicted)

Peak O₂ pulse (% predicted)

HRmax (% predicted)

RER/power slope

Peak VE

Peak breathing frequency

Maximum expiratory pressure

Maximum inspiratory pressure

Submaximal constant work rate exercise test (70% pre-training maximal workload):

Increased

Time and distance until exhaustion

[138]

Results reported refer to statistically significant changes (P < 0.05) compared to before training

6MWT 6-min walk test, HCs healthy controls (exercise-trained), a-vO₂ difference arterial–venous O₂ difference, HR heart rate, HRR heart rate reserve, mtHSP70 mitochondrial 70-kDa heat shock, MnSOD manganese superoxide dismutase, NCAM neural cell adhesion molecule, nMHC neonatal myosin heavy chain, OGG-1 8-oxoguanine DNA glycolase-1, QoL quality of life, RER respiratory exchange ratio, SF-36 36-Item Short Form Survey SGT single-group trial, VAT ventilatory anaerobic threshold, VE pulmonary ventilation