This is a multi-aim study, studying the effects of conventional exercise (measured through Cardiopulomary Exercises Testing or an in-bed pedal exercise) and passive exercise through periodic acceleration (pGz). Aim 1 will focus on the differences between primary mitochondrial disease (PMD) patients and healthy volunteers. Aim 2 is an exploratory aim, which will be studying the effects in patients admitted to the Children's Hospital of Philadelphia Pediatric Intensive Care Unit (PICU).

Aim 1: Primary Mitochondrial Disease Patients and Healthy Controls

Individuals will be screened for eligibility for study entry, and answer questions relating to their ability to perform study procedures and their physical activity levels. Individuals who meet study criteria will have 3 study visits, and each study visit will involve a different intervention.

At each of these study visits, individuals will complete one of the following interventions: Cardiopulmonary Exercise Testing (CPET), pGz administration through a bed or recliner, and pGz through a device called a Gentle Jogger. While participants will complete all three study visits, the order of the study visits will occur in random order.

During the study visits, participants will have blood draws before and after the study intervention, a vascular ultrasound with a Lumason contrast agent before and after the study intervention, and a Creatine Chemical Exchange Saturation Transfer (CrCEST) MRI of the lower leg.

Aim 2: Patients in the Pediatric Intensive Care Unit (PICU)

Individuals will be screened for eligibility for study entry. Individuals who meet study criteria will have 2 study visits during their admission to the PICU. The first study visit will involve a pedal exercise and the second study visit will involve pGz administration through a device called a Gentle Jogger.

During the study visits, participants will have blood draws before and after the study intervention, a vascular ultrasound with a Lumason contrast agent before and after the study intervention, and if able to safely complete, an CrCEST MRI of the lower leg.

Aim 1 Enrollment Criteria Inclusion Criteria for Healthy Controls

• Males or females, 10 years to 60 years, with a minimum height for participation of 135 cm
• Ambulatory and able to complete routine clinical exercise testing
• Willing and able to complete all study procedures
• For individuals under the age of 18, parental/guardian permission (informed consent) and as appropriate, child assent
• For individuals over the age of 18 the ability to provide informed consent

Inclusion Criteria for PMD Patients

• Males or females, 10 years to 60 years, with a minimum height for participation of 135 cm
• Ambulatory and able to complete routine clinical exercise testing
• Willing and able to complete all study procedures
• Genetically confirmed mitochondrial myopathy (MM) as defined by a diagnosis of primary mitochondrial disease (PMD) with predominant symptoms of myopathy as expressed by exercise intolerance and muscle weakness and fatigue
• Parental/guardian permission (informed consent) and as appropriate, child assent

Exclusion Criteria for All Aim 1 Participants General Exclusion Criteria

• Tracheostomy
• Non-ambulatory
• Unable to complete routine exercise testing
• Diagnosed with or have symptoms of vertigo
• Within 1 month of a recent hospital admission for acute illness
• Severe co-existing cardiac or pulmonary disease
• Cognitive impairment that may preclude ability to comply with study procedures
• Pregnant or lactating females
• Active alcohol and/or substance abuse
• At the discretion of the principal investigator (PI), any medical condition that will interfere with or prevent the safe completion of the study
• Parents/guardians or subjects who, in the opinion of the Investigator, may be non-compliant with study schedules or procedures
• Use of investigational agent(s) within 4 weeks
• Individuals who are employed by the U.S. Department of Defense, including U.S military personal
• Patients with biliary atresia with asplenia or polysplenia.
• Patients with prior liver transplant.
• Patients with cystic fibrosis.
• Patients with chronic lung disease.
• Patients with portal vein thrombosis, cavernous transformation of the portal vein or absent portal vein.
• Patients with significant heart disease or severe congenital heart disease.
• Patients with a history of allergic reaction to Lumason®, sulfur hexafluoride, sulfur hexafluoride lipid microsphere components, or other ingredients in Lumason (polyethylene glycol, distearoylphosphatidlycholine (DSPC), dipalmitoylphosphatidylglycerol sodium (DPPG-Na, palmitic acid) or other components of the ultrasound contrast agent
• Any history of intraocular injury or fragment in or around the orbit that cannot be cleared through radiologic evaluation
• Any history of bullet, shrapnel, or stabbing wounds that cannot be cleared through radiologic evaluation
• Past or current employment involving (or exposure to) a metal grinder (e.g., at a construction worksite)
• Claustrophobia or any known medical conditions which can be exacerbated by stress, anxiety, or panic attacks triggered by enclosed spaces
• Inability to lie flat in an MRI scanner for up to 45 minutes
• Unable to perform sub-maximal ankle dorsiflexion leg exercise during the MRI study

Aim 2 Enrollment Criteria Inclusion Criteria for PICU PMD Non-Ambulatory Patients

• Males or females ages 10 to 23 years (children and adults)
• Non-ambulatory
• Genetically confirmed mtDNA-PMD
• Cooperative and capable of following research procedures
• Have cognitive ability to enable cooperation with study procedures
• Admitted to the PICU with an anticipated length of stay for >24 hours
• Willing and able to complete all study procedures
• For individuals under the age of 18, parental/guardian permission (informed consent) and as appropriate, child assent
• For individuals over the age of 18 the ability to provide informed consent

Inclusion Criteria for PICU non-PMD neuromuscular diagnosis

• Males or females ages 10 to 23 years (children and adults)
• Non-ambulatory
• Genetically confirmed non-PMD neuromuscular diagnosis
• Cooperative and capable of following research procedures
• Have cognitive ability to enable cooperation with study procedures
• Admitted to the PICU with an anticipated length of stay for >24 hours
• For individuals under the age of 18, parental/guardian permission (informed consent) and as appropriate, child assent
• For individuals over the age of 18 the ability to provide informed consent

Inclusion Criteria for all other PICU Participants

• Males or females ages 10 to 23 years (children and adults)
• Non-ambulatory
• No known genetic diagnosis with healthy pre-morbid status, admitted to PICU
• Cooperative and capable of following research procedures
• Have cognitive ability to enable cooperation with study procedures
• Admitted to the PICU with an anticipated length of stay for >24 hours
• Willing and able to complete all study procedures
• For individuals under the age of 18, parental/guardian permission (informed consent) and as appropriate, child assent
• For individuals over the age of 18 the ability to provide informed consent

Exclusion Criteria for All Aim 2 Participants

• Have cognitive impairment that may preclude ability to comply with study procedures
• Have cardiorespiratory instability
• Patients in whom are so sick that they will not be able to cooperate with the study procedures
• Have clear contraindications to mobilization
• Have fixed lower limb deformities/contractures that would prohibit lower extremity exercise
• Pregnant or lactating females
• Active alcohol and/or substance abuse
• At the discretion of the principal investigator (PI), any medical condition that will interfere with or prevent the safe completion of the study
• Use of investigational agent(s) within 4 weeks
• Individual who are employed by the U.S. Department of Defense, including U.S military personal
• Patients with biliary atresia with asplenia or polysplenia.
• Patients with prior liver transplant.
• Patients with cystic fibrosis.
• Patients with chronic lung disease.
• Patients with portal vein thrombosis, cavernous transformation of the portal vein or absent portal vein.
• Patients with significant heart disease or severe congenital heart disease.
• Patients with a history of allergic reaction to Lumason®, sulfur hexafluoride, sulfur hexafluoride lipid microsphere components, or other ingredients in Lumason (polyethylene glycol, distearoylphosphatidlycholine (DSPC), dipalmitoylphosphatidylglycerol sodium (DPPG-Na, palmitic acid) or other components of the ultrasound contrast agent

Exclusion Criteria Specific to study procedure: CrCEST MRI Scan:

• Any history of intraocular injury or fragment in or around the orbit that cannot be cleared through radiologic evaluation
• Any history of bullet, shrapnel, or stabbing wounds that cannot be cleared through radiologic evaluation
• Past or current employment involving (or exposure to) a metal grinder (e.g., at a construction worksite)
• Claustrophobia or any known medical conditions which can be exacerbated by stress, anxiety, or panic attacks triggered by enclosed spaces
• Inability to lie flat in an MRI scanner for up to 45 minutes
• Unable to perform sub-maximal ankle dorsiflexion leg exercise during the MRI study